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Interferon-alpha treatment induces depression-like behaviour accompanied by elevated hippocampal quinolinic acid levels in rats
Abstract
Immunotherapy with the cytokine interferon-alpha (IFN-α) can induce symptoms of depression, and it is likely that the tryptophan-kynurenine pathway may be involved in this regard. In this study we investigated the effects of IFN-α on depression-like behaviour and central metabolites of the tryptophan-kynurenine pathway in rats. Secondly, we explored the modulating effects of an antidepressant (imipramine) and anti-inflammatory drug (celecoxib) on IFN-α-induced behavioural and pathophysiological changes in the brain. The following treatment groups were used: Control (saline), IFN-α (6×10(4) IU/kg s.c.), IFN-α + imipramine or IFN-α + celecoxib. Drugs were administered daily for 1 week. IFN-α treatment induced depression-like behaviour by increasing immobility in the forced swim test (FST), and decreased tryptophan levels in the brain. There was a trend for an increased kynurenine/tryptophan ratio, indicative of indoleamine 2,3-dioxygenase (IDO) activation, and increased quinolinic acid in the hippocampus. Imipramine decreased immobility in the FST, but did not reverse the IFN-α-induced changes in the tryptophan-kynurenine pathway. There was a trend for celecoxib to decrease immobility and to reverse the IFN-α-induced increase in the kynurenine/tryptophan ratio. Thus, our study provides further evidence for IFN-α-induced depression-like behaviour through central changes of the tryptophan-kynurenine pathway.
Copyright © 2015. Published by Elsevier B.V.
... de Munter et al. (2020) showed that celecoxib did not affect FST-induced despair in WT mice but in a genetic model of frontotemporal lobar degeneration (FUS[1-359]-tg mice) the drug reduced despair. There was also a tendency for celecoxib to reduce IFN-α induced despair in male S-D rats (Fischer et al., 2015). Guo et al. (2009) found celecoxib to reduce CMS-induced anhedonia in male S-D rats and Kurhe et al. (2014) showed reduced despair and anhedonia in a high-fat diet model of depression in swiss albino mice. ...
... In all studies, independent of the depression model, 29 out of 36 reported antidepressant effects of NSAIDs. The models used were either stress-induced depressive-like behaviour (15 of 29) (Brunello et al., 2006;Guo et al., 2009;Guan et al., 2014;Santiago et al., 2014;Guevara et al., 2015;Luo et al., 2017;Singh et al., 2017;Alboni et al., 2018;Perveen et al., 2018;Qadeer et al., 2018;Seo et al., 2019;Song et al., 2019;Feng et al., 2020;Luo et al., 2020;Stachowicz, 2020), 5 studies were directly related to inflammation (De La Garza et al., 2005;Saleh et al., 2014;Fischer et al., 2015;Mesripour et al., 2019;Salmani et al., 2021), 8 studies used different disease models (Maciel et al., 2013;Martín-de-Saavedra et al., 2013;Borges et al., 2014;Norden et al., 2015;Santiago et al., 2015;Nemeth et al., 2016;Morgese et al., 2018;de Munter et al., 2020) and a single study used diet-induced depression (Kurhe et al., 2014). Six studies failed to find antidepressant effects of NSAIDs. ...
... Interestingly, all studies applying selective COX-2 inhibitors (celecoxib and rofecoxib) reported antidepressant effects of these drugs (Guo et al., 2009;Maciel et al., 2013;Martín-de-Saavedra et al., 2013;Kurhe et al., 2014;Santiago et al., 2014;Fischer et al., 2015;Alboni et al., 2018;Morgese et al., 2018;Mesripour et al., 2019;Song et al., 2019;de Munter et al., 2020;Feng et al., 2020). It has previously been reported that selective COX-2 inhibitors may be more effective in relieving depression than non-selective COX-inhibitors (Baune, 2017). ...
In recent years much focus has been on neuroimmune mechanisms of depression. As a consequence, many preclinical and clinical trials have been performed examining potential antidepressant effects of several anti-inflammatory drugs. The results of such trials have been varied. With the current manuscript we wished to elucidate the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on depressive-like behaviour in rodent models of depression by performing a systematic review of the available literature. We performed a systematic literature search in PubMed for rodent models of depression where NSAIDs were administered and a validated measure of depressive-like behaviour was applied. 858 studies were initially identified and screened using Covidence systematic review software. Of these 36 met the inclusion criteria and were included. The extracted articles contained data from both rat and mouse studies but primarily male animals were used. Several depression models were applied and 17 different NSAIDs were tested for antidepressant effects. Our results suggest that stress models are the best choice when examining antidepressant effects of NSAIDs. Furthermore, we found that rat models provide a more homogenous response than mouse models. Intriguingly, the use of female animals was only reported in three studies and these failed to find antidepressant effects of NSAIDs. This should be explored further. When comparing the different classes of NSAIDs, selective COX-2 inhibitors were shown to provide the most stable antidepressant effect compared to non-selective COX-inhibitors. Suggested mechanisms behind the antidepressant effects were attenuation of neuroinflammation, HPA-axis dysregulation and altered monoamine expression.
... So far, studies on the correlation between inflammatory cytokines and IDO in psychiatric disorders has mainly focused on depression. Although there is no direct evidence, previous studies have found that increased IDO activity, induced by pro-inflammatory cytokines, can lead to the development of depression [25][26][27]. There are few studies on the correlation between IDO and cytokines in schizophrenia, and further studies are needed. ...
... A previous study found that the COX-2 inhibitor celecoxib inhibits IDO-mediated immune tolerance through regulatory T cells [28]. In another study, celecoxib reverses the IFN-α-induced increase in the kynurenine/Trp ratio, indicative of IDO activation [27]. However, it is unclear whether celecoxib is involved in the regulation of IDO activity in schizophrenia. ...
... And this inhibition is associated with T cells [28]. In another animal study, the researchers observed that celecoxib reverses the IFN-α-induced increase in the kynurenine/Trp ratio in rats [27]. In the present study, we found that celecoxib had a significant inhibitory effect on IDO expression. ...
The indoleamine 2,3-dioxygenase (IDO) enzyme is the first rate-limiting enzyme of the tryptophan degradation pathway in which dysfunction of neuroactive metabolites has been implicated in the pathophysiology of schizophrenia. Inflammatory molecules such as pro-inflammatory cytokines could enhance the activity of IDO. There are few studies on the expression of IDO levels and its correlation with levels of inflammatory cytokines in first-episode drug-naive patients with schizophrenia. One hundred inpatients (female = 33, male = 67) with first-episode drug-naive schizophrenia entered a 6-week, double-blind, randomized, placebo-controlled clinical trial. All individuals were assigned celecoxib or placebo combined with risperidone. Serum levels of IDO and six inflammatory cytokines (IL-1β, IL-6, TNF-α IL-17, IL-4, and INF-γ) were measured. The Positive and Negative Syndrome Scale (PANSS) was used to assess the severity of psychotic symptoms. Compared to healthy subjects, patients had significantly elevated levels of IDO and six cytokines at baseline. Over the 6-week treatment period, the decrease in the levels of IDO and TNF-α and the improvement in the PANSS total score, positive scores, and negative scores in the celecoxib group were significantly greater than in the placebo group. There was a significantly positive correlation between IDO levels and the PANSS negative scores and between IDO levels and TNF-α and IFN-γ levels in the celecoxib group. These findings showed abnormal expression of IDO levels which correlated with negative symptoms and pro-inflammatory cytokine levels in patients with first-episode drug-naive schizophrenia, suggesting the important role of IDO in the pathological mechanism of schizophrenia. Registration number: ChiCTR2000041403.
... It was previously shown that Dxt administration prevented interferon-α-induced depression 12 . Interferon-α -induced depression is also related to augmentation of IDO activity, that was prevented by Dxt co-administration 13 . Notably, starting treatment with Dxt/quinidine or increasing the dose to twice daily in resilient depressed patients, has shown rapid mood improvements (1-2 days) in some patients 14 . ...
... Animals were placed in the experimental room 24 hrs before the test for acclimatization. All the experiments were accomplished between 8 [11][12][13][14]. Between the behavioral tests, mice were put back in their home cage with access to food and water. ...
... In all preclinical studies (17/17, 100%), regardless of the depression model, antidepressant effect of celecoxib was reported. Most included reports have pointed to the antidepressant effect of celecoxib in monotherapy [72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87]. Interestingly, two studies indicated that celecoxib might enhance the antidepressant effects of fluoxetine and bupropion [75,88]. ...
... The models used to assess the influence of celecoxib on anxiety or depressive symptoms were as follows: stress-induced depressive-like behavior [73,77,78,81,84,86,88], induced by inflammation [74,79,82,85], diet-induced [76], different disease models [75,80,83], and bulbectomy [72,87]. ...
The effects of celecoxib on a broad spectrum of mood disorders and on inflammatory parameters have not yet been comprehensively evaluated. The aim of this study was to systematically summarize the available knowledge on this topic. Data from both preclinical and clinical studies were analyzed, considering the efficacy and safety of celecoxib in the treatment of mood disorders, as well as the correlation of inflammatory parameters with the effect of celecoxib treatment. Forty-four studies were included. We found evidence supporting the antidepressant efficacy of celecoxib in a dose of 400 mg/day used for 6 weeks as an add-on treatment in major depression (SMD = −1.12 [95%Cl: −1.71,−0.52], p = 0.0002) and mania (SMD = −0.82 [95% CI:−1.62,−0.01], p = 0.05). The antidepressant efficacy of celecoxib in the above dosage used as sole treatment was also confirmed in depressed patients with somatic comorbidity (SMD = −1.35 [95% CI:−1.95,−0.75], p < 0.0001). We found no conclusive evidence for the effectiveness of celecoxib in bipolar depression. Celecoxib at a dose of 400 mg/d used for up to 12 weeks appeared to be a safe treatment in patients with mood disorders. Although an association between celecoxib response and inflammatory parameters has been found in preclinical studies, this has not been confirmed in clinical trials. Further studies are needed to evaluate the efficacy of celecoxib in bipolar depression, as well as long-term studies evaluating the safety and efficacy of celecoxib in recurrent mood disorders, studies involving treatment-resistant populations, and assessing the association of celecoxib treatment with inflammatory markers.
... Rodent animal studies have found that injection of cytokines can induce depressive symptoms such as behavioural despair, and psychomotor retardation [48]. LPS is the main component of the cell wall of Gram-negative bacteria [49]. ...
... IFN-α is suggested to modulate mood by the activation of the pro-inflammatory cytokines that comprise IFN-induced 15 kDa protein, ubiquitin-specific proteinase 18, guanylate-binding protein 3, IL-1, L-6, TNF-α, caspase-4, and caspase-8 or death-activating protein kinases. In addition, IFN-α and IFB-β can activate μ opioid receptor, which increases prostaglandin E2 levels in brain, in turn increases the indoleamine-2,3-dioxygenase (IDO) pathway, which leads to neurotoxicity, finally develops depression [48,55]. ...
Major depressive disorder (MDD) is a common mental health disorder that brings severe disease burden worldwide. Traditional antidepressants are mainly targeted at monoamine neurotransmitters, with low remission rates and high recurrence rates. Ketamine is a noncompetitive glutamate N -methyl- d -aspartate receptor (NMDAR) antagonist, and its rapid and powerful antidepressant effects have come to light. Its antidepressant mechanism is still unclarified. Research found that ketamine had not only antagonistic effect on NMDAR but also strong immunomodulatory effect, both of which were closely related to the pathophysiology of MDD. Although there are many related studies, they are relatively heterogeneous. Therefore, this review mainly describes the immune mechanisms involved in MDD and how ketamine plays an antidepressant role by regulating peripheral and central immune system, including peripheral inflammatory cytokines, central microglia, and astrocytes. This review summarizes the related research, finds out the deficiencies of current research, and provides ideas for future research and the development of novel antidepressants.
... [2] Neurologic adverse effects of IFNa therapy is caused by alterations in tryptophan-kynurenine pathway. [3,4] IFNa increases the indoleamine 2,3-dioxygenase (IDO) activity, which is responsible for tryptophan breakdown to kynurenine. Stimulated IDO expression causes high level of tryptophan to go through the neurotoxic arm of the pathway. ...
... Stimulated IDO expression causes high level of tryptophan to go through the neurotoxic arm of the pathway. [4] Therefore, kynurenine increases and tryptophan concentration available for serotonin synthesis decreases. [5] Kynurenine passes through the blood-brain barrier and breaks to neurotoxic metabolites, such as quinolinic acid, with agonistic effect on N-methyl-D-aspartate receptor (NMDAR). ...
Introduction: Treatment with interferon-alpha (IFNa) can induce depression that is likely the result of its effect on the tryptophan-kynurenine pathway. Kynurenine passes through the blood–brain barrier and breaks to neurotoxic metabolites, such as quinolinic acid, with agonistic effect on N-methyl-D-aspartate receptor (NMDAR). Thus, tryptophan available for serotonin synthesis declines. The aim was to evaluate the effect of NMDAR antagonists on IFNa-induced depression in mice model of despair. Materials and Methods: The total immobility time in the forced swimming test (FST) was assessed as an indicator of depression in mice. Depression was induced by IFNa injection (16 × 105 IU/kg) for 6 consecutive days. The optimum dose of dextromethorphan, memantine, and dizocilpine (MK-801) was administered on the 7 th day following IFNa injection. Results: Immobility time in the FST was increased following IFNa injection (181 s ± 7 vs. control 122 s ± 10, P < 0.05) which indicated depression behavior. Dextromethorphan (15 mg/kg) and MK-801 (0.075 mg/kg) administration reduced the immobility time in IFNa-treated animals (57 s ± 14 and 46 s ± 6, respectively). Memantine (5 mg/kg) reduced the immobility time when it was administered alone but failed to decrease the immobility time induced by IFNa. The animals’ locomotor activity was normal in the experimented groups. Conclusion: Dextromethorphan and MK-801 inhibited IFNa-induced depression. Thus, at least part of IFNa depressive behavior is caused by NMDAR that is stimulated by the production of metabolites in the tryptophan-kynurenine pathway. Administrating NMDAR antagonists should be further evaluated for patients suffering from the neurologic side effects of IFNa. © 2019, Faculty of Pharmaceutical Sciences, Chulalongkorn University. All rights reserved.
... Furthermore, increased levels of inflammatory cytokines reduce the synthesis and availability of serotonin via their enhancing effect on the activity of indoleamine 2,3-dioxygenase 1 (IDO1) [14]. Many studies have demonstrated that the upregulation of IDO1 by proinflammatory cytokines induces depressive-like behaviors [15,16]. A recent study identified the IDO1-dependent neurotoxic kynurenine metabolism as a pathogenic factor for cognitive dysfunction in inflammation-induced depressive disorders and a potential novel target for the treatment of these disorders [17]. ...
... Many studies have demonstrated that proinflammatory cytokines have an important role in the development of PSD [13,14]. Inflammatory cytokines reduce serotonin levels via the upregulation of IDO1 [14], which induces depressive-like behaviors [15,16]. In this study, we observed an increased IDO1 immunoreactivity in the nucleus accumbens, hippocampus, and hypothalamus, but not in the striatum of PSD mice (Figure 3). ...
Aim:
Poststroke depression (PSD), which occurs in approximately one-third of stroke survivors, is clinically important because of its association with slow functional recovery and increased mortality. In addition, the underlying pathophysiological mechanisms are still poorly understood.
Methods:
We used a mouse model of PSD to examine the neurobiological mechanisms of PSD and the beneficial effects of aripiprazole, an atypical antipsychotic drug. PSD was induced in mice by combining middle cerebral artery occlusion (MCAO) with spatial restraint stress. The body weight, sucrose preference, and forced swim tests were performed at 5, 7, and 9 weeks and the Morris water maze test at 10 weeks after completing MCAO and spatial restraint stress.
Results:
Mice subjected to MCAO and spatial restraint stress showed significant depressive-like behavior in the sucrose preference test and forced swim test as well as cognitive impairment in the Morris water maze test. The PSD-like phenotype was accompanied by an indoleamine 2,3-dioxygenase 1 (IDO1) expression increase in the nucleus accumbens, hippocampus, and hypothalamus, but not in the striatum. Furthermore, the increased IDO1 levels were localized in Iba-1(+) cells but not in NeuN(+) or GFAP(+) cells, indicating that microglia-induced IDO1 expression was prominent in the PSD mouse brain. Moreover, 3-hydroxyanthranilate 3,4-dioxygenase (HAAO), quinolinic acid (QUIN), and reactive oxygen species (ROS) were significantly increased in the nucleus accumbens, hippocampus, and hypothalamus of PSD mice. Importantly, a 2-week aripiprazole (1 mg/kg, per os) regimen, which was initiated 1 day after MCAO, ameliorated depressive-like behavior and impairment of cognitive functions in PSD mice that was accompanied by downregulation of IDO1, HAAO, QUIN, and ROS.
Conclusions:
Our results suggest that the IDO1-dependent neurotoxic kynurenine metabolism induced by microglia functions in PSD pathogenesis. The beneficial effect of aripiprazole on depressive-like behavior and cognitive impairment may be mediated by inhibition of IDO1, HAAO, QUIN, and ROS.
... Another study reported that central QUIN levels were elevated in mice that were injected with lipopolysaccharide in the peripheral blood . Likewise, rats which received interferon-alpha treatment presented with elevated hippocampal QUIN levels (Fischer et al., 2015). Therefore, the findings from these animal model studies corroborate our main findings. ...
... On the other hand, it has been reported that inflammation may play an important role in the KYN pathway. Animal model studies have revealed relationships between inflammation and the KYN pathway, reporting elevation in central QUIN levels of lipopolysaccharide-injected mice and increase in hippocampal QUIN levels of interferon-alpha treated rats (Fischer et al., 2015). Therefore, our results of lower KYNA levels and higher QUIN levels in depression may be consistent with the mechanism of the KYN pathway under inflammatory conditions. ...
Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant-free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed.
... IFN, interferon; TNF, tumor necrosis factor; IL, interleukin; P2X7, two-transmembrane ATP-gated ionotropic purinoreceptor; CVD, cardiovascular disease; LPS, lipopolysaccharide; PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; CNS, central nervous system; TBI, traumatic brain injury; IDO, indoleamine 2, 3-dioxygenase enzyme; KP, kynurenine pathway. and subsequently attenuate depressive-like symptoms (Tikka et al., 2001;Fischer et al., 2015;Zheng et al., 2015). Imipramine has been shown to reduce the number of chronic stress induced-activated hippocampal microglia (Iwata et al., 2016), perhaps by selectively inhibiting the M1 polarization of microglia (Kobayashi et al., 2013). ...
... Indeed, some recent studies have shown that treatment with antidepressants Imipramine or Minocycline decreases IFN-γ levels by inhibiting microglial activation and subsequently reduces the depressive symptoms in animal models of depression (Fischer et al., 2015;Zheng et al., 2015). Studies involving a transgenic IL-1 receptor antagonist have shown to reduce microglial apoptosis and subsequently neuroinflammation and depressive-like behavior in rodents (Goshen et al., 2008;Koo and Duman, 2009;Kreisel et al., 2014a). ...
Depression has been widely accepted as a major psychiatric disease affecting nearly 350 million people worldwide. Research focus is now shifting from studying the extrinsic and social factors of depression to the underlying molecular causes. Microglial activity is shown to be associated with pathological conditions, such as psychological stress, pathological aging, and chronic infections. These are primary immune effector cells in the CNS and regulate the extensive dialogue between the nervous and the immune systems in response to different immunological, physiological, and psychological stressors. Studies have suggested that during stress and pathologies, microglia play a significant role in the disruption of neuroplasticity and have detrimental effects on neuroprotection causing neuroinflammation and exacerbation of depression. After a systematic search of literature databases, relevant articles on the microglial regulation of bidirectional neuroimmune pathways affecting neuroplasticity and leading to depression were reviewed. Although, several hypotheses have been proposed for the microglial role in the onset of depression, it is clear that all molecular pathways to depression are linked through microglia-associated neuroinflammation and hippocampal degeneration. Molecular factors such as an excess of glucocorticoids and changes in gene expression of neurotrophic factors, as well as neuro active substances secreted by gut microbiota have also been shown to affect microglial morphology and phenotype resulting in depression. This review aims to critically analyze the various molecular pathways associated with the microglial role in depression.
... Dysregulation in levels of several kynurenine pathway metabolites has been described in depression and other psychiatric disorders. For example, increased levels of QUIN have been detected in animal models of depressive-like behavior [19], in hepatitis C patients with depression induced by IFN- [20] and in the cerebrospinal fluid (CSF) of suicide attempters [21], who have also been shown to have reduced PIC and a decreased PIC/QUIN ratio in both CSF and blood [22]. Similarly, increased levels of kynurenine have been detected in depression induced by IFN- [23] and in the hippocampus of patients with Alzheimer's disease [24], while the peripheral ratio of kynurenic acid/QUIN ratio has been shown to be reduced in depressed individuals [25,26]. ...
... However, no effect of monoaminergic antidepressants was observed on levels of metabolites secreted by blood from depressed patients stimulated in vitro by LPS [57]. Likewise, evaluations in animals have shown that imipramine reduced the initially elevated kynurenine/tryptophan ratio in the hippocampus of rats exposed to LPS or chronic mild stress [58], but caused no metabolite changes in a related study where the depression-like behavior was induced by IFN-α [19]. The regulation of kynurenine enzymes has also been measured: fluoxetine had no effect on KMO mRNA levels when used to prevent the development of depressive-like behavior in a mouse model of cancer related fatigue [59], while agomelatine, a melatonergic antidepressant, reversed the LPS-dependent increase in KMO expression in the hippocampus of rats [60]. ...
Both increased inflammation and reduced neurogenesis have been associated with the pathophysiology of major depression. We have previously described how interleukin-1 (IL-1) β,a pro-inflammatory cytokine increased in depressed patients, decreases neurogenesis in human hippocampal progenitor cells. Here, using the same human in vitro model, we show how omega-3 (ω-3) polyunsaturated fatty acids and conventional antidepressants reverse this reduction in neurogenesis, while differentially affecting the kynurenine pathway. We allowed neural cells to proliferate for 3 days and further differentiate for 7 days in the presence of IL-1β (10 ng/ml) and either the selective serotonin reuptake inhibitor sertraline (1 µM), the serotonin and norepinephrine reuptake inhibitor venlafaxine (1 µM), or the ω-3 fatty acids eicosapentaenoic acid (EPA, 10 µM) or docosahexaenoic acid (DHA, 10 µM). Co-incubation with each of these compounds reversed the IL-1β-induced reduction in neurogenesis (DCX- and MAP2-positive neurons), indicative of a protective effect. Moreover, EPA and DHA also reversed the IL-1β-induced increase in kynurenine, as well as mRNA levels of indolamine-2,3-dioxygenase (IDO); while DHA and sertraline reverted the IL-1β-induced increase in quinolinic acid and mRNA levels of kynurenine 3-monooxygenase (KMO). Our results show common effects of monoaminergic antidepressants and ω-3 fatty acids on the reduction of neurogenesis caused by IL-1β, but acting through both common and different kynurenine pathway-related mechanisms. Further characterization of their individual properties will be of benefit towards improving a future personalized medicine approach.
... Thus, there is increasing interest in the role of TRP metabolites and the kynurenine pathway (KP) as well as the serotonin pathway in MDD [8][9][10][11][12][13][14]. There are multiple studies regarding the relationship between IDO1 and MDD [15,16], but there are few reports on the role of kynurenine 3-monooxygenase (KMO). KMO is a pivotal enzyme in KP and normally oxidizes KYN to 3-hydroxykynurenine in the presence of nicotinamide adenine dinucleotide phosphate (NADPH) and molecular oxygen. ...
... Compared with the WT mice, the concentrations of KYN, KA, and AA dramatically increased, but the concentrations of 3-HAA and 3-HK decreased. Many studies have demonstrated that the upregulation of IDO1 by proinflammatory cytokines induces depressive-like behaviors [10,13,14,16,32,33]. In addition, these behavioral phenotypes were not observed in the IDO1 KO mice [34] as they were protected from inflammationinduced depressive-like behavior. ...
l-Tryptophan (TRP) is metabolized via serotonin and kynurenine pathways (KP). Several studies have demonstrated that abnormality of both pathways is involved in the pathogenesis of major depressive disorder (MDD). Kynurenine 3-monooxygenase (KMO), a pivotal enzyme in the KP, has been suggested to play major roles in physiological and pathological events mediated by bioactive kynurenine metabolites. In this study, we investigated the role of KMO in the emotional and cognitive functions by using KMO knockout (KO) mice. We measured contents of TRP and monoamines and their metabolites in the serum and hippocampus of KMO KO mice. Further, we investigated whether antidepressants improved the depressive-like behaviors in KMO KO mice.
... Briefly, quinolinic acid promotes an excessive release of glutamate while inhibiting the astroglial neurotransmitter reuptake, raising the extracellular concentrations of glutamate, generating excessive excitatory synapses, which culminate in excitotoxicity due to an exacerbated increase in calcium (Ca 2+ ) influx [24]. This influx of Ca 2+ leads to neuronal mitochondrial dysfunction, with the activation of caspases and proteases, which, together with the action of nitric oxide synthase, promote apoptosis [25]. ...
... Indeed, it has been shown that nearly 50% of patients treated with IFN-α develop depression [46,47] and that IFN-α can also induce depression in animal models. [48] IFN-α is a potent activator of the inflammatory cytokine network that activates IL-1, IL-6, and TNF-α, causing depressive symptoms. [49,50] This mechanism involves inflammatory factors that can lead to: altered glucocorticoid receptor function [51] ; substantial alterations in the activity of the diurnal hypothalamic-pituitary-adrenal axis, including flattening of adrenocorticotropic hormone levels, diurnal fluctuations in cortisol, increased nocturnal adrenocorticotropic hormone and cortisol levels [52] ; and decreased levels of brain derived neurotrophic factors. ...
We aimed to investigate the related risk factors of depression in patients with chronic obstructive pulmonary disease (COPD) to detect depressed patients early and perform timely intervention to improve the disease prognosis of chronic obstructive pulmonary disease. This cross-sectional study included COPD patients who were discharged from the First People’s Hospital of Hefei, China from October 2018 to October 2019, and all participants were diagnosed with COPD according to the Global Initiative for Chronic Obstructive Pulmonary Disease. There was no COPD exacerbation during follow-up 1 month after discharge. Psycho-cognitive disorders, psychiatric disorders or other conditions causing psychiatric symptoms were excluded. We divided stable patients with chronic obstructive pulmonary disease into depression group (HAM-D 24 ≥ 8) and non-depression group (<8), and compared the sociodemographic data, clinical characteristics and serum inflammatory parameters between the 2 groups. In this cross-sectional study, 100 eligible COPD patients were initially recruited, 64 of whom completed all the programs. Univariate logistic regression analysis, female, chronic obstructive pulmonary disease assessment test (CAT) score, serum interferon alpha-a (IFN-α) level, and low smoking index were associated with depression in patients with chronic obstructive pulmonary disease. Multivariate logistic regression analysis showed that high serum IFN-α level (OR = 1.099, 95% CI: 1.010–1.196; P = .028), high CAT score (OR = 1.250, 95% CI: 1.052–1.484; P = .011) and low smoking index (OR = 10.154, 95% CI: 1.886–54.664; P = .007) were significant risk factors for depression in patients with chronic obstructive pulmonary disease. Our findings suggest that high serum IFN-α levels, and high CAT scores are risk factors for comorbid depression in COPD patients. Continuous high-dose smoking may aggravate the primary disease and ultimately aggravate depression.
... Many recent studies have indicated that chronic inflammation is related to depression and mood disorders in patients [40,54]. IFNα is a well-known inducer of depression and has been studied in various models [55,56]. IFN triggers the induction of indolamine 2,3-dioxygenase (IDO) and results in higher tryptophan metabolism along the kynurenine pathway and less being available for conversion to 5-hydroxytryptophan that induces the serotonin pathway; decreased serotonin levels lead to depression. ...
Excessive production and response to Type I interferons (IFNs) is a hallmark of systemic lupus erythematosus (SLE). Neuropsychiatric lupus (NPSLE) is a common manifestation of human SLE, with major depression as the most common presentation. Clinical studies have demonstrated that IFNα can cause depressive symptoms. We have shown that the kallikrein–kinin system (KKS) [comprised of kallikreins (Klks) and bradykinins] and angiotensin-converting enzyme inhibitors suppressed Type I IFN responses in dendritic cells from lupus-prone mice and human peripheral blood mononuclear cells. Tissue Klk genes are decreased in patients with lupus, and giving exogenous Klk1 ameliorated kidney pathology in mice. We retro-orbitally administered mouse klk1 gene-carrying adenovirus in the Murphy Roths Large lymphoproliferative (MRL/lpr) lupus-prone mice at early disease onset and analyzed immune responses and depressive-like behavior. Klk1 improved depressive-like behavior, suppressed interferon-responsive genes and neuroinflammation, and reduced plasma IFNα levels and proinflammatory cytokines. Klk1 also reduced IFNAR1 and JAK1 protein expression, important upstream molecules in Type I IFN signaling. Klk1 reduced bradykinin B1 receptor expression, which is known to induce proinflammatory response. Together, these findings suggest that Klk1 may be a potential therapeutic candidate to control IFNα production/responses and other inflammatory responses in SLE and NPSLE.
... In the same studies, it was observed that imipramine, an antidepressant, reduced depressivelike behaviors without reducing changes in the tryptophan-kynurenine pathway. At the same time, celecoxib, an anti-inflammatory, tended to mitigate depressive-like behaviors and the hippocampal kynurenine/tryptophan ratio (Fischer et al. 2015). ...
Major depressive disorder (MDD) is a prevalent psychiatric disorder that has damage to people’s quality of life. Tryptophan is the precursor to serotonin, a critical neurotransmitter in mood modulation. In mammals, most free tryptophan is degraded by the kynurenine pathway (KP), resulting in a range of metabolites involved in inflammation, immune response, and neurotransmission. The imbalance between quinolinic acid (QA), a toxic metabolite, and kynurenic acid (KynA), a protective metabolite, is a relevant phenomenon involved in the pathophysiology of MDD. Proinflammatory cytokines increase the activity of the enzyme indoleamine 2,3-dioxygenase (IDO), leading to the degradation of tryptophan in the KP and an increase in the release of QA. IDO activates proinflammatory genes, potentiating neuroinflammation and deregulating other physiological mechanisms related to chronic stress and MDD. This review highlights the physiological mechanisms involved with stress and MDD, which are underlying an imbalance of the KP and discuss potential therapeutic targets.
... The kynurenine pathway of tryptophan metabolism begins when tryptophan is degraded into kynurenine under regulation of the enzyme indoleamine 2,3-dioxygenase (IDO). Indeed, previous work from our group and others have highlighted that inflammatory cytokines, such as IL-1, IL-6, TNF- and IFN-, can induce IDO and subsequently promote degradation of tryptophan down the kynurenine pathway (27,31,(33)(34)(35). Additionally, IL-1 has been further revealed to activate the enzymes 3-monooxygenase (KMO) and kynureninase (KYNU), which are involved in the production of further kynurenine pathway metabolites, such as anthranilic acid, 3-hydroxykynrenine acid (3-HK), and eventually the neurotoxic quinolinic acid ( Figure 1) (31). ...
Background
Understanding the precise mechanisms of ketamine is crucial for replicating its rapid antidepressant effects without inducing psychomimetic changes. Here, we explore whether the antidepressant-like effects of ketamine enantiomers are underscored by protection against cytokine-induced reductions in hippocampal neurogenesis and activation of the neurotoxic kynurenine pathway, in our well-established in vitro model of depression in a dish.
Methods
We used the fetal hippocampal progenitor cell line (HPC0A07/03C) to investigate ketamine’s impact on cytokine-induced reductions in neurogenesis in vitro. Cells were treated with interleukin- 1beta (IL-1b) (10 ng/ml) or IL-6 (50 pg/ml), alone or in combination with ketamine enantiomers, arketamine (R-ketamine, 400 nM) or esketamine (S-ketamine, 400 nM), or antidepressants, sertraline (1 mM) or venlafaxine (1mM).
Results
Resembling the effect of antidepressants, both ketamine enantiomers prevented IL-1b- and IL-6-induced reduction in neurogenesis and increase in apoptosis. This was mediated by inhibition of IL-1b-induced production of IL-2 and IL-13 by R-ketamine, and of IL1b-induced tumour necrosis factor-alpha (TNF-a) by S-ketamine. Likewise, R-ketamine inhibited IL-6-induced production of IL-13, whereas S-ketamine inhibited IL-6-induced IL-1b and IL-8. Moreover, both R- and S-ketamine prevented IL-1b-induced increases in indoleamine 2,3-dioxygenase (IDO) expression as well as kynurenine production, which in turn was shown to mediate the detrimental effects of IL-1b on neurogenesis and apoptosis. In contrast, neither R- nor S-ketamine prevented IL-6-induced kynurenine pathway activation.
Conclusions
Results suggest that R- and S-ketamine have pro-neurogenic and anti-inflammatory properties, however, this is mediated by inhibition of the kynurenine pathway only in the context of IL-1b. Overall, this study enhances our understanding of the mechanisms underlying ketamine’s antidepressant effects in the context of different inflammatory phenotypes, ultimately leading to the development of more effective, personalised therapeutic approaches for patients suffering from depression.
... Since, IDO induction by IFN-α, causes 5-HT deficiency because of the shift of tryptophan metabolism to kynurenine formation 28 . Kynurenine, which is capable of crossing the blood-brain barrier, can be metabolized into quinolinic acid -a neurotoxic agent that stimulates the NMDA receptor 29 . In our investigation, Lav200 altered depressive-like behavior caused by IFN-α and the results were comparable with fluoxetine. ...
... First, a pretest of 15 min (for habituations), and then a test for 5 min following drug treatment (Slattery & Cryan, 2012;Stratinaki et al., 2013) is administered. Swim sessions were video recorded and the immobility, swimming, and climbing behaviors were scored at the end of each test session (Cryan, et al., 2005;Fischer et al., 2015;Pereira et al., 2015) and timed using a stopwatch. The 5-min test was scored by a trained blind observer (Castagné et al., 2010). ...
Introduction:
The model for screening antidepressant-like activity in pre-clinical drug studies include, rat forced swimming test (FST). The reports on N-acetylcysteine (NAC) as an antioxidant supplement in stress related disorder is well documented. This study was aimed at potential antidepressant mechanism of N-Acetyl Cysteine (NAC), a glutamate precursor on FST animal model for screening antidepressant drugs using fluoxetine, a selective serotonin reuptake inhibitors (SSRIs) as standard antidepressant drug.
Methods:
Thirty adult male Wistar rats used for this study were randomly divided into six groups each with five (n=5) rats. The control group (A) received 1 ml of normal saline daily, group B served as the FST model, group C received 200mg/kg/day of NAC, group D received 20mg/kg/day of fluoxetine, group E the FST model treated with 200mg/kg/day of NAC, and F is the FST model treated with 20mg/kg/day of fluoxetine. Drugs were given orally. The effects of NAC on brain weights, the FST paradigms, sucrose preference test (SPT) for anhedonia were assessed and data analyzed using ANOVA where Tukey post-hoc test for statistical significance was set at (p < 0.05). The brains fixed in 4% paraformaldehyde, were processed and the paraffin embedded tissue were serially sectioned at 5 μm thick to be stained using Haematoxylin and Eosin (H and E) stain, immuno-histochemistry for synaptophysin (p38) and astrocytes (GFAP) activities in the prefrontal cortex (PFC).
Results:
Findings showed that NAC prevented FST-induced anxiety-like behaviors demonstrated by an increased SPT (that alleviates anhedonia), mobility time, and reduced immobility time. NAC caused an increase in brain weights and prevented FST-induced neurodegeneration, the proliferation of reactive astrocytes, and diminished synaptophysin immunoreactivity in the PFC similar to that seen in fluoxetine a standard anti-depressant drug.
Conclusion:
NAC treatment significantly exhibits its neuroprotective mechanism via inhibiting the proliferation of reactive astrocytes, which protects neurons and synapses from oxidative tissue damage induced by FST, hence an increase in synaptophysin activity that culminates in increased neural activity, increased SPT, and reduced immobility time.
... However, chronic rimonabant treatment reduced sucrose consumption and increased immobility time in the FST (Beyer et al., 2010). For IFN-α treatment, there are reports showing that acute and chronic treatment regimes in rodents increase immobility in the FST (Fischer et al., 2015;Makino et al., 1998Makino et al., , 2000Ping et al., 2012) and reduce sucrose preference (Ping et al., 2012), as well as reports that show no effect (De La Garza et al., 2005). This adds to growing evidence that traditionally used preclinical tests such as the FST and SPT may not be the most reliable and lack aspects of validity for detecting pro-depressant or antidepressant efficacy across drugs with a range of pharmacological actions (Planchez et al., 2019). ...
Studies in human and non‐human species suggest that decision‐making behaviour can be biased by affective state, also termed an affective bias. To study these behaviours in non‐human species, judgement bias tasks have been developed. Animals are trained to associate specific cues (tones) with a positive or negative/less positive outcome. Animals are then presented with intermediate ambiguous cues and affective biases quantified by observing whether animals make more optimistic or more pessimistic choices. Here we use a high versus low reward judgement bias task and test whether pharmacologically distinct compounds, which induce negative biases in learning and memory, have similar effects on decision‐making: tetrabenazine (0.0‐1.0mg/kg), retinoic acid (0.0‐ 10.0mg/kg) and rimonabant (0.0‐10.0mg/kg). We also tested immunomodulatory compounds: interferon‐α (0‐ 100units/kg), lipopolysaccharide (0.0‐10.0μg/kg) and corticosterone (0.0‐10.0mg/kg). We observed no specific effects in the judgement bias task with any acute treatment except corticosterone which induced a negative bias. We have previously observed a similar lack of effect with acute but not chronic psychosocial stress and so next tested decision‐making behaviour following chronic interferon‐alpha. Animals developed a negative bias which was sustained even after treatment was ended. These data suggest that decision‐making behaviour in the task is sensitive to chronic but not acute effects of most pro‐depressant drugs or immunomodulators, but exogenous administration of acute corticosterone induces pessimistic behaviour. This work supports our hypothesis that biases in decision‐making develop over a different temporal scale to those seen with learning and memory which may be relevant in the development and perpetuation of mood disorders.
... These findings suggest that IDO1 activation is an important feature of depressive-like states induced by inflammatory processes. Preclinical, in vitro, and postmortem data have demonstrated that elevation of KYN metabolites levels is also associated with neuronal damage and/or suppression of neurogenesis (Fischer et al., 2015). We demonstrated that LPS disturbed KYN metabolites in the PFC. ...
Indoleamine 2,3‐dioxygenase 1 (IDO1) is the first rate‐limiting enzyme that metabolizes tryptophan to the kynurenine pathway. Its activity is highly inducible by pro‐inflammatory cytokines and correlates with the severity of major depressive disorder (MDD). MicroRNAs (miRNAs) are involved in gene regulation and the development of neuropsychiatric disorders including MDD. However, the role of miRNAs in targeting IDO1 in the pathophysiology of MDD is still unknown. In this study, we investigated the role of novel miRNAs in the regulation of IDO1 activity and its effect on lipopolysaccharide (LPS)‐induced depression‐like behavior in mice. LPS up‐regulated miR‐874‐3p concomitantly with increase in IDO1 expression in the prefrontal cortex (PFC), increase in immobility in the forced swimming test as depression‐like behavior and decrease in locomotor activity as sickness behavior without motor dysfunction. The miR‐874‐3p increased in both neuron and microglia after LPS. Its mimic significantly suppressed LPS‐induced IDO1 expression in the PFC. Infusion of IDO1 inhibitor (1‐methyl‐l‐tryptophan) and miR‐874‐3p into PFC prevented an increase in immobility in the forced swimming test, but did not decrease in locomotor activity induced by LPS. These results suggest that miR‐874‐3p may play an important role in preventing the LPS‐induced depression‐like behavior through inhibition of IDO1 expression. This may also serve as a novel potential target molecule for the treatment of MDD.
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... In contrast, elevation of inflammatory markers is associated with a poor response to antidepressants (Strawbridge et al., 2019). Substrates that induce inflammation such as interferon-α and LPS induce depression in humans and depression-like behavior in animals (Couch et al., 2016;Fischer et al., 2015;Hepgul et al., 2018). Consistent with the role of inflammation in depression, administration of cytokine inhibitors such as TNF-α antagonists (e.g. ...
Emotional disorders like anxiety and depression are responsible for considerable morbidity and mortality all over the world. Several antidepressant and anxiolytic medications are available for the treatment of anxiety and depression. However, a significant number of patients either do not respond to these medications or respond inadequately. Hence, there is a need to identify novel targets for the treatment of anxiety and depression. In this review we focus on the renin angiotensin system (RAS) as a potential target for the treatment of these disorders. We review work that has evaluated the effects of various compounds targeting the RAS on anxiety-and depression-like behaviors. Further, we suggest future work that must be carried out to fully exploit the RAS for the treatment of anxiety and depression. The RAS provides an attractive target for both the identification of novel anxiolytic and antidepressant medications and/or for enhancing the efficacy of currently available medications used for the treatment of anxiety and depression.
... Increased IFNα levels have been shown in the CSF of NPSLE patients (68). IFNα is known to reduce serotonin by skewing the tryptophan-kyneurinine pathway (69). Circulating serotonin levels have been shown to be indicative of kidney disease in lupus (24) as well as an indicator of depression (23,70). ...
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE, often causing depression. Interferon-α (IFNα) is a central mediator in disease pathogenesis. Administration of IFNα to patients with chronic viral infections or cancers causes depressive symptoms. Angiotensin-converting enzyme (ACE) is part of the kallikrein–kinin/renin-angiotensin (KKS/RAS) system that regulates many physiological processes, including inflammation, and brain functions. It is known that ACE degrades bradykinin (BK) into inactive peptides. We have previously shown in an in vitro model of mouse bone-marrow-derived dendritic cells (BMDC) and human peripheral blood mononuclear cells that captopril (a centrally acting ACE inhibitor-ACEi) suppressed Type I IFN responsive gene (IRG) expression. In this report, we used the MRL/lpr lupus-prone mouse model, an established model to study NPSLE, to determine the in vivo effects of captopril on Type I IFN and associated immune responses in the periphery and brain and effects on behavior. Administering captopril to MRL/lpr mice decreased expression of IRGs in brain, spleen and kidney, decreased circulating and tissue IFNα levels, decreased microglial activation (IBA-1 expression) and reduced depressive-like behavior. Serotonin levels that are decreased in depression were increased by captopril treatment. Captopril also reduced autoantibody levels in plasma and immune complex deposition in kidney and brain. Thus, ACEi’s may have potential for therapeutic use for systemic and NPSLE.
... The relationship between DA, its receptors and the immune system is bidirectional. Indeed, immune system activation and the resulting release of inflammatory cytokines can negatively affect reward behavior, motivation, anxiety and DA, which can be identified as depression-like behavior in animals (Fischer et al. 2015;Kamata et al. 2000;Kaster et al. 2012;Kitagami et al. 2003;Makino et al. 2000;Remus and Dantzer 2016;Shuto et al. 1997;Simen et al. 2006;Wachholz et al. 2017) and depressive symptoms in patients (Capuron et al. 2012;Capuron et al. 2007;Eisenberger et al. 2010;Goldsmith et al. 2016a;Majer et al. 2008). Nevertheless, to our knowledge no induction of mania-like behavior via activation of the immune system have been reported yet (Beyer and Freund 2017;van Enkhuizen et al. 2015;Kato et al. 2007;Logan and McClung 2016;Sharma et al. 2016). ...
Background - Prefrontal dopamine D1 receptor (D1R) mediates behavior related to anxiety, reward and memory, and is involved in inflammatory processes, all of which are affected in bipolar disorder. Patients with bipolar disorder show alternations in the dopamingergic and immune system. Interleukin-6 (IL-6), a pro-inflammatory cytokine, is increased in plasma samples, imaging studies and post mortem tissue. Manipulation of the D1R in the medial prefrontal cortex (mPFC) e.g. results in BD-like behavior. The purpose of the study is the investigation of the influence of D1R over-expression and its termination on the immune system and anxiety behavior in rats.
Methods – Expression of the gene for D1R in glutamatergic neurons within the mPFC of male, adult rats was manipulated through an inducible (Tet.On) lentiviral vector. Anxiety behavior was studied in the elevated plus maze and marble burying test in ‘ON’ (D1R over-expression) and ‘OFF’ (termination of D1R over-expression) states. IL-6-positive cells were counted to identify the inflammatory state within several subregions of the hippocampus.
Results - D1R ‘OFF’ subjects buried more marbles compared to D1R ‘ON’ and their respective control animals indicating an increased anxiety behavior. D1R ‘OFF’ animals reflected an elevated pro-inflammatory state in the hippocampus, in the CA3 and dentate gyrus especially. Consistently, inflammatory state in the whole hippocampus and anxiety behavior correlated positively, indicating a connection between anxiety and inflammatory state of the hippocampus.
Conclusions – Behavioral and molecular findings support the association of D1R’s impact on anxiety and inflammation. In addition, by confirming an involvement of IL-6, the new animal model for bipolar disorder has been further validated.
... Preclinical studies in rats [146] and in mice [147] confirmed that KYN pathway activation was one of the pathophysiologic underpinnings of interferon-alpha induced depression. Interestingly, a recent study in schizophrenics showed a link between KYN pathway activation and attention/ cognitive deficits commonly observed in these patients [148]. ...
Tryptophan (TRP), an essential amino acid in mammals, is involved in several physiological processes including neuronal function, immunity, and gut homeostasis. In humans, TRP is metabolized via the kynurenine and serotonin pathways, leading to the generation of biologically active compounds, such as serotonin, melatonin and niacin. In addition to endogenous TRP metabolism, resident gut microbiota also contributes to the production of specific TRP metabolites and indirectly influences host physiology.
The variety of physiologic functions regulated by TRP reflects the complex pattern of diseases associated with altered homeostasis. Indeed, an imbalance in the synthesis of TRP metabolites has been associated with pathophysiologic mechanisms occurring in neurologic and psychiatric disorders, in chronic immune activation and in the immune escape of cancer. In this chapter, the role of TRP metabolism in health and disease is presented. Disorders involving the central nervous system, malignancy, inflammatory bowel and cardiovascular disease are discussed.
... Furthermore, pro-inflammatory cytokines (e.g., interferon) have been demonstrated to mediate the enzymatic activity of the kynurenine pathway [45], resulting in decreased neuroprotective effects for kynurenic acid. This result is consistent with the findings that interferon-induced depression iñ 50% of patients receiving interferon treatment [46] and that interferon treatment resulted in decreased levels of tryptophan and increased levels of kynurenine and quinolinic acid in the rodent brain [47,48]. Finally, antiinflammatory treatments have been reported to decrease depressive symptoms in patients [49]. ...
Major depressive disorder (MDD) is a serious mental illness, characterized by high morbidity, which has increased in recent decades. However, the molecular mechanisms underlying MDD remain unclear. Previous studies have identified altered metabolic profiles in peripheral tissues associated with MDD. Using curated metabolic characterization data from a large sample of MDD patients, we meta-analyzed the results of metabolites in peripheral blood. Pathway and network analyses were then performed to elucidate the biological themes within these altered metabolites. We identified 23 differentially expressed metabolites between MDD patients and controls from 46 studies. MDD patients were characterized by higher levels of asymmetric dimethylarginine, tyramine, 2-hydroxybutyric acid, phosphatidylcholine (32:1), and taurochenodesoxycholic acid and lower levels of l-acetylcarnitine, creatinine, l-asparagine, l-glutamine, linoleic acid, pyruvic acid, palmitoleic acid, l-serine, oleic acid, myo-inositol, dodecanoic acid, l-methionine, hypoxanthine, palmitic acid, l-tryptophan, kynurenic acid, taurine, and 25-hydroxyvitamin D compared with controls. l-tryptophan and kynurenic acid were consistently downregulated in MDD patients, regardless of antidepressant exposure. Depression rating scores were negatively associated with decreased levels of l-tryptophan. Pathway and network analyses revealed altered amino acid metabolism and lipid metabolism, especially for the tryptophan–kynurenine pathway and fatty acid metabolism, in the peripheral system of MDD patients. Taken together, our integrated results revealed that metabolic changes in the peripheral blood were associated with MDD, particularly decreased l-tryptophan and kynurenic acid levels, and alterations in the tryptophan–kynurenine and fatty acid metabolism pathways. Our findings may facilitate biomarker development and the elucidation of the molecular mechanisms that underly MDD.
... Moreover, at a transcriptome level, LPS and PIC were found to regulate a different set of genes [44]. Therefore, future studies will be necessary to determine if (R,S)-ketamine is effective against a range of peripheral inflammatory stressors such as Interleukin 1 (IL-1) [45], TNF-α [46], or interferon alpha (IFN-α) [47]. ...
Individuals with peripheral inflammation are a particularly vulnerable population for developing depression and are also more resistant towards traditional antidepressants. This signals the need for novel drugs that can effectively treat this patient population. Recently, we have demonstrated that (R,S)-ketamine is a prophylactic against a variety of stressors, but have yet to test if it is protective against inflammatory-induced vulnerability to a stressor. Here, male 129S6/SvEv mice were administered saline or (R,S)-ketamine (30 mg/kg) 6 days before an injection of vehicle (VEH) or lipopolysaccharide (LPS) (0.83 or 1.0 mg/kg, serotypes O111:B4 or O127:B8). Twenty-four hours after LPS administration, mice were administered a contextual fear conditioning (CFC) paradigm, followed by a context re-exposure and the forced swim test (FST). In a separate cohort, we tested if (R,S)-ketamine was effective as a prophylactic against polyinosinic-polycytidylic acid (PIC), a viral mimetic. (R,S)-ketamine was effective as a prophylactic for attenuating learned fear in the O111:B4 and O127:B8 strains of LPS. (R,S)-ketamine was also effective as a prophylactic for decreasing stress-induced depressive-like behavior in the O111:B4 and O127:B8 strains of LPS. Both of these effects were limited to administration of 1.0, but not 0.83 mg/kg of the O111:B4 and O127:B8 strains of LPS. (R,S)-ketamine was not effective against either stress phenotype following PIC administration. These data suggest that prophylactic (R,S)-ketamine may protect against selective inflammation-induced stress phenotypes following an inflammatory challenge. Future studies will be necessary to determine if (R,S)-ketamine can be useful in patient populations with peripheral inflammation.
... Sickness and depressive behaviors triggered by inflammation have been abrogated and attenuated by antiinflammatory agents [209,214,215]. For example, nonsteroidal anti-inflammatory drugs (NSAIDs), including diclofenac and celecoxib, have been shown to modulate and reverse IFN-alphainduced depressive symptoms [216,217]. In addition, Karson and colleagues found that chronic administration of a TNF-α inhibitor reduced depression and anxiety-like behavior in CMS model of depression in rats [218]. ...
Depression is a highly prevalent psychiatric condition, with over 300 million sufferers, and is an important comorbidity for other conditions, like cardiovascular disorders or diabetes. Therapy is largely based on psychotherapy and/or pharmacological intervention, particularly aimed at altering neurotransmitter levels in the central nervous system, but inadequate response to treatment remains a significant clinical problem. Herein, evidence supporting a molecular link between inflammation and depression will be discussed, particularly the increased prevalence of depression in chronic inflammatory diseases and the evidence on the use of anti-inflammatory drugs to treat depression. Moreover, the potential for the levels of peripheral inflammatory molecules to act as depression biomarkers, in the diagnosis and monitoring of depression will be examined, considering clinical- and animal model-based evidence.
... The FST was developed accordingly to previous works (Porsolt et al., 1977). First, animals were placed individually to swim in acrylic cylinders (24 cm diameter by 60 cm height containing 40 cm of water at 24 ± 1°C) for 15 min (pre-test) (Fischer et al., 2015;Pereira et al., 2015). After 24 h, the animals were exposed to a 5-min session in the open-field test (OFT) immediately followed by a 5-min FST session. ...
Objective
Treatment-resistance to antidepressants is a major problem in the pharmacotherapy of major depressive disorder (MDD). Unfortunately, only a few animal models are suitable for studying treatment-resistant depression, among them repeated treatment with ACTH appears to be useful to mimic treatment-resistance to monoaminergic antidepressants. Therefore, the present work aimed to investigate the effectiveness of s-ketamine and rapastinel (formerly GLYX13), modulators of the glutamatergic N-methyl-D-aspartate (NMDA) receptor in ACTH-treated animals.
Methods
Naïve male Sprague Dawley rats were subjected to repeated subcutaneous injections with ACTH (100 µg/0.1mL/rat/day) for 14 days and drug treatment on the test day (open field and forced swim test) with imipramine, s-ketamine or rapastinel. In addition, assessment of plasma levels of corticosterone and ACTH was carried out.
Results
We found that rats repeatedly treated with ACTH for 14 days responded to single injections with s-ketamine (15 mg/kg) and rapastinel (10 mg/kg), but failed to respond to imipramine (15 mg/kg). In the plasma, the levels of corticosterone and ACTH were increased after 14 days of daily treatment with ACTH, independently of the treatment.
Conclusion
The present data confirms development of a resistance to treatment following chronic ACTH administration. In addition, the study confirms the possible effectiveness of s-ketamine and rapastinel as treatment options in treatment resistant depression. Moreover, it highlights the importance of the glutamatergic system in the neurobiology of depression. Further studies are necessary to evaluate how repeated treatment with ACTH leads to a depressed condition resistant to monoaminergic antidepressants.
... Again, this relationship could be due to an over-stimulation of kynurenine pathway, especially via IDO activation, caused by inflammatory cytokines (Russell et al. 2018). A preclinical study by Fischer et al. (2015) found that IFN-alpha administration induced depressive symptoms (measured with the forced swim test) in rats and an increased K/T ratio. However, while imipramine administration seemed to improve depressive-like behavior without acting on the tryptophan-kynurenine pathway, treatment with celecoxib Table 2 List of studies specifically examining the role of the kynurenine pathway in linking depression and cancer ...
Depression is a common comorbidity in cancer cases, but this is not only due to the emotional distress of having a life-threatening disease. A common biological mechanism, involving a dysregulated immune system, seems to underpin this comorbidity. In particular, the activation of the kynurenine pathway of tryptophan degradation due to inflammation may play a key role in the development and persistence of both diseases. As a consequence, targeting enzymes involved in this pathway offers a unique opportunity to develop new strategies to treat cancer and depression at once. In this work, we provide a systematic review of the evidence up to date on the kynurenine pathway role in linking depression and cancer and on clinical implications of this evidence. In particular, complications due to chemotherapy are discussed, as well as the potential antidepressant efficacy of novel immunotherapies for cancer.
... In addition, IA-induced depression may also involve neurotrophic factors [13]. Data have been reported showing that depression-like behavior induced by IA administration is accompanied by increases in quinolinic acid in the hippocampus in rats [25]. IA-induced depression in mice has also been shown to involve impairment to neurogenesis in the hippocampus [58]. ...
The effects of chronic (17 days) intranasal administration of low (50 IU/kg) and intermediate (8000 IU/kg) doses of human interferon-α (IA) on behavioral indicators of anxiety and depression and the monoaminergic system of the brain were studied in rats. Control rats received the same volume of intranasal physiological saline. IA was found to have any ambiguous effects on anxiety levels. Thus, anxiety in the open field test increased after administration of both doses of IA and decreased in the light-dark test and elevated plus maze test after small doses of IA. In the forced swimming test, administration of both doses of IA was followed by an increase in the duration of immobility (a behavioral symptom of depression). Administration of the intermediate (but not the small) dose of IA was followed by increases in the contents of dopamine and its metabolites in the olfactory bulb and decreases in the nucleus accumbens; the noradrenaline content decreased in the prefrontal cortex. It is suggested that these neurochemical changes in the brain may underlie the behavioral symptoms of depression induced by intranasal administration of intermediate doses of IA. Depression-like behavioral symptoms occurring after administration of small doses of IA were evidently not linked with changes in brain monoaminergic systems but could be due to other mechanisms.
... A number of indings suggest that the neuropsychiatric side efects observed during IFN-α therapy may be linked to aberrations in the tryptophan (TRP)-kynurenine (KYN) pathway [8,9]. Clinical studies have found that IFN-α therapy reduces plasma TRP and serotonin (5-hydroxythrptamine; 5-HT) levels [8] and increases KYN levels in plasma and cerebrospi- nal luid (CSF). ...
Hepatitis C virus (HCV) infection afects approximately 170 million people worldwide.
Interferon-alpha (IFN-α) is a cytokine that is related to early viral infection and has both
antiviral and antiproliferative properties. The current standard treatment for long-term
chronic hepatitis C (CHC) consists of combination therapy with IFN-α and ribavirin,
which has a broad spectrum antiviral efect. Despite the potential therapeutic beneits of
IFN-α, its administration often causes many side efects, such as somatic and neuropsychiatric
symptoms. Depression is a serious and frequently occurring side efect of IFN-α
therapy, and this is one of the major reasons for cessation of the therapy. Therefore, in
order to avoid the discontinuation of INF-α therapy owing to depressive symptoms, it
is important to identify the risk factor(s) leading to the onset of associated depressive
symptoms. In this chapter, we introduce our novel indings on the association between
IFN treatment and the onset of depression in CHC patients as well as the potential neurobiological
mechanisms by which depression may arise. We also highlight a potential
approach for predicting the onset risk of depression as a side efect in these patients.
... Analysis of potential vulnerability factors has shown that the patients at risk to develop major depression experience a threefold higher increase of circulating ACTH and cortisol levels in response to the first administration of IFN-α than resilient patients (17). Peripheral (132) and central (133) administration of IFN-α to mice causes depression-like behavior (133), and long-term administration of LPS to rats produces a specific cytokine response in the brain characterized by increased IL-1β and IFN-γ levels (100). Inoculation of mice with Bacille Calmette-Guérin, an attenuated form of Mycobacterium bovis, induces depression-like behavior, an effect that is absent in IFN-γ receptor knockout mice while an acute episode of sickness behavior persists (134). ...
Stress refers to a dynamic process in which the homeostasis of an organism is challenged, the outcome depending on the type, severity, and duration of stressors involved, the stress responses triggered, and the stress resilience of the organism. Importantly, the relationship between stress and the immune system is bidirectional, as not only stressors have an impact on immune function, but alterations in immune function themselves can elicit stress responses. Such bidirectional interactions have been prominently identified to occur in the gastrointestinal tract in which there is a close cross-talk between the gut microbiota and the local immune system, governed by the permeability of the intestinal mucosa. External stressors disturb the homeostasis between microbiota and gut, these disturbances being signaled to the brain via multiple communication pathways constituting the gut–brain axis, ultimately eliciting stress responses and perturbations of brain function. In view of these relationships, the present article sets out to highlight some of the interactions between peripheral immune activation, especially in the visceral system, and brain function, behavior, and stress coping. These issues are exemplified by the way through which the intestinal microbiota as well as microbe-associated molecular patterns including lipopolysaccharide communicate with the immune system and brain, and the mechanisms whereby overt inflammation in the GI tract impacts on emotional-affective behavior, pain sensitivity, and stress coping. The interactions between the peripheral immune system and the brain take place along the gut–brain axis, the major communication pathways of which comprise microbial metabolites, gut hormones, immune mediators, and sensory neurons. Through these signaling systems, several transmitter and neuropeptide systems within the brain are altered under conditions of peripheral immune stress, enabling adaptive processes related to stress coping and resilience to take place. These aspects of the impact of immune stress on molecular and behavioral processes in the brain have a bearing on several disturbances of mental health and highlight novel opportunities of therapeutic intervention.
... The animals were exposed to the FST accordingly to previous works (Porsolt et al., 1977). In short, animals were placed individually to swim in plastic cylinders (24 cm diameter by 60 cm height containing 40 cm of water at 24 ± 1°C) for 15 min (pre-test) (Fischer et al., 2015;Pereira et al., 2015). After 24 h, the animals were exposed to a 5-min session of forced swim (test). ...
The rapid and sustained antidepressant properties of ketamine provide evidence of the importance of the glutamatergic system in the neurobiology of depression. The antidepressant-like effects of ketamine are dependent on brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR) in limbic brain areas. The nitrergic system is closely related to the glutamatergic system and generates antidepressant-like effects when blocked. The aim of this study was to investigate whether the behavioural effects induced by the inhibition of nitric oxide (NO) synthesis by aminoguanidine or N-methyl-D-aspartate (NMDA) receptor blockade by ketamine would affect the gene expression of Bdnf and Mtor in the ventromedial prefrontal cortex in rats. The effects of ketamine or aminoguanidine were investigated in Sprague-Dawley (SD) rats, the Flinders Sensitive Line (FSL), a genetic rat model of depression, and their controls, the Flinders Resistant Line (FRL) rats. In the studies, the three protocols evaluated to which the animals/rats were exposed were: (1) pre-test and test sessions of forced swim test (FST), (2) pre-test session of FST alone, or (3) not exposed to the FST. Ketamine and aminoguanidine both induce antidepressant-like effects in SD and FSL rats. Quantitative real-time polymerase chain reaction analyses in SD rats demonstrated that none of the treatments can change the Bdnf or Mtor gene expression, but in FSL rats the treatment with ketamine increased only Bdnf gene expression. The data obtained strengthens the role of NMDA antagonists and NO inhibitors as potential antidepressant drugs, albeit with different effects on Bdnf gene expression.
... However, a large Mendelian randomisation study found no causal association between increased CRP levels and depression in people with genetically elevated CRP [108], and also that inflammation may better stratify those who will or will not benefit from antiinflammatory treatments [109]. More compelling is the strong observation of depressive symptoms induced by interferon-α treatment, both in humans and in animal models [110][111][112][113]. ...
Depression remains a debilitating condition with an uncertain aetiology. Recently, attention has been given to the renin–angiotensin system. In the central nervous system, angiotensin II may be important in multiple pathways related to neurodevelopment and regulation of the stress response. Studies of drugs targeting the renin–angiotensin system have yielded promising results. Here, we review the potential beneficial effects of angiotensin blockers in depression and their mechanisms of action. Drugs blocking the angiotensin system have efficacy in several animal models of depression. While no randomised clinical trials were found, case reports and observational studies showed that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had positive effects on depression, whereas other antihypertensive agents did not. Drugs targeting the renin–angiotensin system act on inflammatory pathways implicated in depression. Both preclinical and clinical data suggest that these drugs possess antidepressant properties. In light of these results, angiotensin system-blocking agents offer new horizons in mood disorder treatment.
... The FST was developed accordingly to previous works (Porsolt et al., 1977). First, animals were placed individually to swim in acrylic cylinders (24 cm diameter by 60 cm height containing 40 cm of water at 24 ± 1°C) for 15 min (pre-test) (Fischer et al., 2015;Pereira et al., 2015). After 24 h, the animals were exposed to a 5-min session in the open-field test (OFT) immediately followed by a 5-min FST session. ...
... Therefore, IFN-α treatment may directly and/or indirectly stimulate IDO1 induction and thereby promote the KYN pathway, which results in increased levels of neuroactive compounds and an imbalance of TRP metabolites in the brain. Neuroactive TRP metabolites such as 3-HK, QUIN, and KA may promote oxidative stress, cell death, and excessive glutamate release that can cause neuronal damage and behavioral changes 45,46 . More experiments blocking KYN metabolizing enzymes, e.g., kynurenine-3-monooxygenase (KMO) or kynurenine aminotransferase II (KAT II), will clarify whether KYN induces depressive-like behavior by itself or after further generation of its downstream neuroactive metabolites. ...
Depression is known to occur frequently in chronic hepatitis C viral (HCV) patients receiving interferon (IFN)-α therapy. In this study, we investigated whether indoleamine 2,3-dioxygenase1 (IDO1)-mediated tryptophan (TRP) metabolism plays a critical role in depression occurring as a side effect of IFN-α therapy. Increases in serum kynurenine (KYN) and 3-hydroxykynurenine (3-HK) concentrations and in the ratios of KYN/TRP and 3-HK/kynurenic acid (KA) were much larger in depressive HCV patients than in non-depressed patients following therapy. Furthermore, transfection of a plasmid continuously expressing murine IFN-γ into normal mice significantly increased depression-like behavior. IFN-γ gene transfer also resulted in a decrease in serum TRP levels in the mice while KYN and 3-HK levels were significantly increased in both serum and frontal cortex. Genetic deletion of IDO1 in mice abrogated both the increase in depression-like behavior and the elevation in TRP metabolites’ levels, and the turnover of serotonin in the frontal cortex after IFN-γ gene transfer. These results indicate that the KYN pathway of IDO1-mediated TRP metabolism plays a critical role in depressive symptoms associated with IFN-α therapy.
... This neurotoxic challenge causes a reduction in the density of serotonergic and adrenergic neuron, and loss of neurons in the hippocampus. These neurochemical and neurohistological changes predispose to depression [28,44,[47][48][49]. ...
Background
Depression is among the commonest of psychiatric disorders, and inflammatory mechanisms have been suggested to play a role in its pathophysiology. Interferons are a superfamily of proinflammatory cytokines that play a role in host defence mechanisms. Interferons are used in the treatment of a variety of autoimmune (e.g. multiple sclerosis), viral (e.g. chronic hepatitis B and C), and malignant (e.g. malignant melanoma, hairy cell leukemia) disorders; depression, however, is a notable and clinically troublesome adverse effect.
Objective
This article seeks to present a simple explanation and update for the reader about what interferons are, how interferons are classified, the clinical conditions in which interferons are used, the occurrence of depression as a clinical adverse effect of interferon therapy, possible mechanisms that explain interferon-related depression, the treatment of interferon-related depression, and the prevention of interferon-related depression.
Methods
A qualitative literature review is presented.
Results and Conclusions
Irrespective of the indication for IFN therapy, IFNs are associated with a 30-70% risk of treatment-emergent depression. This risk could be due to the IFN, or to an interaction between the IFN and the indication for which it was prescribed. Various neurohormonal, neurochemical, neurohistological, and other mechanisms have been put forth to explain IFN-related depression. Prophylactic treatment with antidepressants reduces the risk of IFN-related depression; antidepressants also effectively treat the condition. Recent alternatives to IFNs have shown to decrease the risk of treatment-emergent depression.
... Also data from rhesus monkeys that were treated with IFN-a on a daily basis showed depressive-like behavior after chronic administration over four weeks (Felger et al., 2007). In a rat model, depressive-like behavior in the FST occurred after daily application of IFN-a over one week of treatment (Fischer et al., 2015). These findings indicate a translational effect of IFN-a over several species and enhances its relevance as an animal model for human immune mediated depression. ...
Inflammatory immune activation has been frequently associated with the development of major depression. This association was confirmed in patients receiving long-term treatment with pro-inflammatory interferon-α (IFN-α). Microglia, the resident immune cells in the brain, might serve as an important interface in this immune system-to-brain communication. The aim of the present study was to investigate the role of microglia in an IFN-α mouse model of immune-mediated depression. Male BALB/c mice were treated with daily injections of IFN-α for two weeks. Depressive-like behavior was analyzed in the forced swim and tail suspension test. Activation of microglia was measured by flow cytometry. Pro-inflammatory M1 type (MHC-II, CD40, CD54, CD80, CD86, CCR7), anti-inflammatory M2 type (CD206, CD200R), and maturation markers (CD11c, CCR7) were tested, as well as the chemokine receptor CCR2. IFN-α led to a significant increase in depressive-like behavior and expression of the pro-inflammatory surface markers MHC-II, CD86, and CD54, indicating M1 polarization. Because IFN-α-treated mice showed great individual variance in the behavioral response to IFN-α, they were further divided into vulnerable and non-vulnerable subgroups. Only IFN-α vulnerable mice (characterized by their development of depressive-like behavior in response to IFN-α) showed an increased expression of MHC-II and CD86, while CD54 was similarly enhanced in both subgroups. Thus, IFN-α-induced activation of microglia was specifically associated with depressive-like behavior.
... The potentil role of kynurenine pathway inhibitors like Leflunomide in the management of depression has been documented (Hazari and Bhad, 2015). Imipramine is salso a antidepressant drug used to reverse the INF-α-induced increase in the kynurenine/tryptophan ratio in rats (Fischer et al., 2015). Recentaly, oleanolic acid derivatives viz. ...
Background
Interferon-alpha (IFN-α) is a useful therapy for some types of cancers and viral infections. Cyclosporine A (CSA) is an immunosuppressant drug used to reduce the risk of graft rejection. Chronic use of IFN-α and CSA are related to psychological symptoms such as depression. Vanillic acid (VA) is a naturally occurring flavoring substance with antidepressant potential. The aim of this study was to evaluate the effect of VA on depression caused by these two drugs in a mice model.
Materials and Methods
Male Swiss mice (25–30 g) were used. Depression was induced by IFN-α 1600000 IU/kg, sc for six days, or CSA20 mg/kg, ip for 3 days as VA 25 mg/kg, and pretreatment was ip injected. After evaluating the locomotor activity, depression was assessed by forced swimming test (FST) and sucrose preference (SP) test.
Results
The selected treatments did not cause significant changes in the locomotor activity. IFN-α significantly increased the immobility time during FST (184.5 ± 12.9 s vs. vehicle 107.1 ± 11.4s) indicating depressive-like effect, and VA pretreatment reversed it (94.8 ± 17.8 s vs. IFN-α), SP increased to 76%. CSA also increased the immobility time during FST (160.3 ± 3.4 s vs. vehicle 113.2 ± 7.6 s; P < 0.05), VA pretreatment reduced it (81.8 ± 16.9 s, vs. cyclosporine; P < 0.001), and SP increased from 38% to 75%. SP results were in agreement with FST results.
Conclusion
VA showed useful effect against IFN-α and cyclosporine-induced depression in mice. Further clinical studies regarding VA antidepressant effect in patients receiving IFN-α or CSA are warranted.
Background
Depression is the most common comorbidities associated with rheumatoid arthritis (RA). We aimed to explore the mechanism of association between RA and depression.
Methods
120 subjects were enrolled and depression was diagnosed and assessed using DSM-5 and 24-item version of Hamilton Depression Scale. Pain intensity and joint function in patients with RA were assessed using the visual analogue scale (VAS) and health assessment questionnaire (HAQ). Serum levels of interferon-gamma (IFN-γ), indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), tryptophan (TRP), and quinolinic acid (QUIN)were detected. In animal experiments, K/BxN mice with RA-like phenotype was used and depressive behavior was observed. The protein expression level of N-methyl -D- aspartate receptor 2B (NR2B) in the hippocampus was detected.
Results
In this study, 36.67% of patients with RA also had depression. The working status, month family income, tender joint count, the VAS and HAQ score were the main factors influencing the depression in RA patients. HAQ score was found to be an independent risk factor for depression in RA. Serum IDO, IFN-γ, KYN were increased and TRP contents were decreased in RA group. K/BxN mice with RA-like phenotype showed depressive behavior. However, injection of IFN-γ neutralizing antibody could inhibit kynurenine pathway and reverse the depressive behavior in mice. The levels of QUIN in the neurotoxic metabolic pathway were increased and N-methyl -D- aspartate receptors (NMDAR) were activated, which may be the mechanism behind the onset of depression.
Conclusions
From clinical and preclinical aspects, the occurrence of depression in RA was explored and the related mechanism was revealed.
The present study evaluated the antidepressant-like effects of vilazodone using the tail suspension test in mice. We also investigated the contribution of kynurenine pathway and N-methyl-d-aspartate receptors to this effect. For this purpose, we pretreated animals with sub-effective doses of L-kynurenine, 3-hydroxykynurenine, or quinolinic acid. We then assessed the immobility time, an indicative measure of depressive-like behavior, in the tail suspension test. We also evaluated the possible effects of sub-effective doses of vilazodone combined with sub-effective doses of ketamine (N-methyl-d-aspartate receptor antagonist) in a separate group. Vilazodone (3 mg/kg, intraperitoneal) significantly reduced immobility time in the tail suspension test. L-kynurenine (1.7 mg/kg, intraperitoneal), 3-hydroxykynurenine (10 mg/kg, intraperitoneal), and quinolinic acid (3 nmol/site, intracerebroventricular) significantly increased the immobility time in the tail suspension test. The antidepressant-like effects of vilazodone (3 mg/kg, intraperitoneal) were inhibited by pre-treatment with non-effective doses of L-kynurenine (0.83 mg/kg, intraperitoneal), 3-hydroxykynurenine (3.33 mg/kg, intraperitoneal), or quinolinic acid (1 nmol/site, intracerebroventricular). Pretreatment of mice with sub-effective doses of ketamine (1 mg/kg, intraperitoneal) optimized the action of a sub-effective dose of vilazodone (0.3 mg/kg, intraperitoneal) and reduced the immobility time in the tail suspension test. None of the drugs used in this study induced any changes in locomotor activity in the open field test. The results showed that vilazodone induced an antidepressant-like effect in the tail suspension test, which may be mediated through an interaction with the kynurenine pathway and N-methyl-d-aspartate receptors.
The kynurenine pathway (KP), a major route of tryptophan catabolism, may be associated with the pathophysiology of depressive disorders. KP is responsible for ca. 99% of brain tryptophan metabolism via its degradation to kynurenine (KYN) catalyzed by indoleamine 2,3-dioxygenase (IDO). Some cytokines, such as interferon-γ (IFN-γ) and interleukin (IL)-6 are potent inducers of IDO. KYN is further converted by kynurenine aminotransferase (KAT) to the more neuroprotective kynurenic acid or by kynurenine 3-monooxygenase (KMO) to neurotoxic 3-hydroxykynurenine. The aim of the present study was to delineate whether the administration of imipramine (IMI) to rats subjected to chronic mild stress (CMS) may reverse behavioral changes induced by CMS in association with changes in immune-inflammatory markers and KP. We confirmed that the CMS procedure modeled one of the main symptoms of depression, i.e. anhedonia, and administration of IMI for 5 weeks resulted in a significant reduction in anhedonia in a majority of animals (CMS IMI-R animals), whereas 20% of animals did not respond to IMI treatment (CMS IMI-NR animals). We established that CMS procedure increased IFN-γ and IDO mRNA and decreased KAT II mRNA expression in the rat cortex. In the cortex and hippocampus, IMI treatment and non-responsiveness to IMI (in CMS IMI-NR animals) were associated with increased IL-6 mRNA expression. In the spleen, CMS increased production of IFN-γ and IL-6 proteins, while these cytokines were decreased by IMI in CMS IMI-R animals. Chronic IMI administration to CMS rats decreased IDO and KMO mRNA and protein expression and increased KAT II/KMO mRNA and protein ratio in IMI responders (CMS IMI-R) in comparison to CMS rats. In CMS IMI-NR rats, a significant increase in IDO mRNA expression and protein level in comparison with IMI responders was observed. Our findings indicate that resistance to therapeutic action of IMI could be explained by a deficiency of the inhibitory properties of IMI on IDO, KMO and KYN synthesis in the cortex. We conclude that the antidepressant activity of IMI may, at least in part, be explained by modulatory activities on the KAT II/KMO ratio in brain areas.
Objective
Interferon-α (IFN) therapy can cause depressive symptom which may lead to drug discontinuation. By interfering with tryptophan pathway, the available level of tryptophan required for serotonin synthesis decreases which could be related to depression. The aim of this study was to evaluate whether soybean diet could improve IFN-induced depression.
Materials and Methods
Male mice weighing 28±3 g were used in the forced swimming test (FST) as an animal model of depression; also, locomotor activity was recorded. IFN 16×105 IU/kg was injected subcutaneously for 6 days. Animals were fed with regular diet or soybean diet at 3 concentrations throughout the experiment. Fluoxetine was the reference drug. To check whether the tryptophan content in the soy bean diet was effective, a group of animals was injected with a single dose of tryptophan on the test day.
Results
IFN-α increased the immobility time in the FST (192 sec ± 5.4), that denotes depression in mice. Soybean diets caused less immobility that was more profound with 50% soybean (26.4 sec ± 6). This diet overcame the depression caused by IFN in the FST (54 sec±18). This result was parallel with that of tryptophan injected to animals (38 sec±17). All the animals showed normal locomotor activity.
Conclusion
For the first time, we showed that soybean diet could counteract with depression caused by IFN-α. Since tryptophan therapy had similar effects, possibly the tryptophan content of soybean had induced the serotonin synthesis. Thus, not only less harmful kynurenine was produced but also more serotonin was available in the brain to overcome depression. However, this interpretation needs further evaluations.
Background:
Inflammation may play a significant role in the pathogenesis of depression, although the molecular target for the treatment of inflammation-mediated depressive symptoms remains to be elucidated. Recent studies have implicated the NLRP3 inflammasome in various psychiatric disorders, including depression. However, the underlying mechanism by which NLRP3 inflammasome activation mediates the progression of depressive-like behaviors remains poorly understood.
Methods:
We examined whether NLRP3 deficiency influenced depressive-like behaviors and cerebral inflammation following systemic administration of lipopolysaccharide in mice. To further assess the contribution of the NLRP3 inflammasome to the progression of depression, we evaluated the effects of NLRP3 signaling on levels of indoleamine 2,3-dioxygenase.
Results:
Nlrp3-deficient mice exhibited significant attenuation of depressive-like behaviors and cerebral caspase-1 activation in a lipopolysaccharide-induced model of depression. Treatment with the antidepressant amitriptyline failed to block NLRP3-dependent activation of caspase-1, but inhibited lipopolysaccharide-promoted production of interleukin-1β mRNA via suppressing NF-κB signaling in mouse mixed glial cultures. Interestingly, lipopolysaccharide administration produced NLRP3-dependent increases in indoleamine 2,3-dioxygenase expression and activity of mouse brain. Furthermore, inflammasome-activating stimulations, but not treatment with the inflammasome product interleukin-1β, triggered indoleamine 2,3-dioxygenase mRNA induction in mixed glial cells.
Conclusions:
Our data indicate that the NLRP3 inflammasome is significantly implicated in the progression of systemic inflammation-induced depression. NLRP3-dependent caspase-1 activation produced significant increases in indoleamine 2,3-dioxygenase levels, which may play a significant role in lipopolysaccharide-induced depression. Collectively, our findings suggest that indoleamine 2,3-dioxygenase is a potential downstream mediator of the NLRP3 inflammasome in inflammation-mediated depressive-like behaviors.
Inflammation and depression are closely inter-related to each other, inflammation inducing symptoms of depression and conversely depressed mood and stress favor an inflammatory phenotype. The mechanisms that mediate the ability of inflammation to induce symptoms of depression are intensively studied at the preclinical level. This review discusses how it has been possible to build animal models of inflammation-induced depression based on clinical data and to explore critical mechanisms downstream of inflammation. Namely, we focus on the ability of inflammation to increase the activity of the tryptophan degrading enzyme, indoleamine 2,3 dioxygenase, which leads to the production of kynurenine and downstream neuroactive metabolites. By acting on glutamatergic neurotransmission these neuroactive metabolites play a key role in the development of depression-like behaviors. An important outcome of the preclinical research on inflammation-induced depression is the identification of potential novel targets for antidepressant treatments, which include targeting the kynurenine system and production of downstream metabolites, altering transport of kynurenine into the brain, and modulating glutamatergic transmission.
Importance
Several studies have reported antidepressant effects of anti-inflammatory treatment; however, the results have been conflicting and detrimental adverse effects may contraindicate the use of anti-inflammatory agents.Objective
To systematically review the antidepressant and possible adverse effects of anti-inflammatory interventions.Data Sources
Trials published prior to December, 31, 2013, were identified searching Cochrane Central Register of Controlled Trials, PubMed, EMBASE, PsychINFO, Clinicaltrials.gov, and relevant review articles.Study Selection
Randomized placebo-controlled trials assessing the efficacy and adverse effects of pharmacologic anti-inflammatory treatment in adults with depressive symptoms, including those who fulfilled the criteria for depression.Data Extraction and Synthesis
Data were extracted by 2 independent reviewers. Pooled standard mean difference (SMD) and odds ratios (ORs) were calculated.Main Outcomes and Measures
Depression scores after treatment and adverse effects.Results
Ten publications reporting on 14 trials (6262 participants) were included: 10 trials evaluated the use of nonsteroidal anti-inflammatory drugs (NSAIDs) (n = 4258) and 4 investigated cytokine inhibitors (n = 2004). The pooled effect estimate suggested that anti-inflammatory treatment reduced depressive symptoms (SMD, −0.34; 95% CI, −0.57 to −0.11; I2 = 90%) compared with placebo. This effect was observed in studies including patients with depression (SMD, −0.54; 95% CI, −1.08 to −0.01; I2 = 68%) and depressive symptoms (SMD, −0.27; 95% CI, −0.53 to −0.01; I2 = 68%). The heterogeneity of the studies was not explained by differences in inclusion of clinical depression vs depressive symptoms or use of NSAIDs vs cytokine inhibitors. Subanalyses emphasized the antidepressant properties of the selective cyclooxygenase 2 inhibitor celecoxib (SMD, −0.29; 95% CI, −0.49 to −0.08; I2 = 73%) on remission (OR, 7.89; 95% CI, 2.94 to 21.17; I2 = 0%) and response (OR, 6.59; 95% CI, 2.24 to 19.42; I2 = 0%). Among the 6 studies reporting on adverse effects, we found no evidence of an increased number of gastrointestinal or cardiovascular events after 6 weeks or infections after 12 weeks of anti-inflammatory treatment compared with placebo. All trials were associated with a high risk of bias owing to potentially compromised internal validity.Conclusions and Relevance
Our analysis suggests that anti-inflammatory treatment, in particular celecoxib, decreases depressive symptoms without increased risks of adverse effects. However, a high risk of bias and high heterogeneity made the mean estimate uncertain. This study supports a proof-of-concept concerning the use of anti-inflammatory treatment in depression. Identification of subgroups that could benefit from such treatment might be warranted.
Objectives
The present study examined the hypothesis that combined exposure to repeated challenge using low doses of lipopolysaccharide (LPS) and chronic mild stress (CMS) together This combined exposure is thought to expose the animals to more realistic challenges, testable on different levels (behavioral, neurochemical, immunohistochemical and gene expression). The role of glial cells was examined, as well. Additionally, the effects of chronic administration of tricyclic antidepressant, imipramine and anti-TNF-α, pentoxyphylline were investigated.
Methods
Wistar rats were exposed to either repeated LPS (50 μg/kg i.p.) over 2 weeks, CMS protocol for 4 weeks or LPS over 2 weeks then 4 weeks CMS. Two groups of rats were exposed to LPS/CMS protocol and treated with either imipramine or pentoxifylline. Rats were examined for behavioral, neurochemical and gene expression changes.
Results
Animals exposed to LPS/CMS elaborated depressive-like symptoms with significant increase in both serum corticosterone and TNF-α level compared to saline, LPS or CMS groups. Hippocampal kynurenine/tryptophan ratio and TNF-α gene expression showed significant increase in the LPS/CMS model compared to saline, LPS or CMS groups. The immunohistochemical findings, scrutinized the topography of the examined effects. Chronic treatment with imipramine or pentoxifylline significantly ameliorated the behavioral, neurochemical, immunohistochemical and TNF-α gene expression changes induced by the LPS/CMS protocol.
Conclusion
This study gave a clue to the neurobiological processes underlying, at least subtypes of depressive disorders. It highlighted the possible interactions between stress and immune-inflammatory pathways in the pathogenesis of depression and suggested a new animal model of depression that addresses these pathways.
New neurons generated by the neural stem cells (NSCs) in the adult hippocampus play an important role in emotional regulation and respond to the action of antidepressants. Depression is a common and serious side effect of interferon-α (IFN-α), which limits its use as an antiviral and antitumor drug. However, the mechanism(s) underlying IFN-induced depression are largely unknown. Using a comprehensive battery of behavioral tests, we found that mice subjected to IFN-α treatment exhibited a depression-like phenotype. IFN-α directly suppressed NSC proliferation, resulting in the reduced generation of new neurons. Brain-specific mouse knockout of the IFN-α receptor prevented IFN-α-induced depressive behavioral phenotypes and the inhibition of neurogenesis, suggesting that IFN-α suppresses hippocampal neurogenesis and induces depression via its receptor in the brain. These findings provide insight for understanding the neuropathology underlying IFN-α-induced depression and for developing new strategies for the prevention and treatment of IFN-α-induced depressive effects.
The kynurenine pathway (KP) is the main route of tryptophan degradation whose final product is NAD(+). The metabolism of tryptophan can be altered in ageing and with neurodegenerative process, leading to decreased biosynthesis of nicotinamide. This fact is very relevant considering that tryptophan is the major source of body stores of the nicotinamide-containing NAD(+) coenzymes, which is involved in almost all the bioenergetic and biosynthetic metabolism. Recently, it has been proposed that endogenous tryptophan and its metabolites can interact and/or produce reactive oxygen species in tissues and cells. This subject is of great importance due to the fact that oxidative stress, alterations in KP metabolites, energetic deficit, cell death, and inflammatory events may converge each other to enter into a feedback cycle where each one depends on the other to exert synergistic actions among them. It is worth mentioning that all these factors have been described in aging and in neurodegenerative processes; however, has so far no one established any direct link between alterations in KP and these factors. In this review, we describe each kynurenine remarking their redox properties, their effects in experimental models, their alterations in the aging process.
Studies show that administration of interferon (IFN)-α causes a significant increase in depressive symptoms. The enzyme indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) into kynurenine (KYN) and which is stimulated by proinflammatory cytokines, may be implicated in the development of IFN-α-induced depressive symptoms, first by decreasing the TRP availability to the brain and second by the induction of the KYN pathway resulting in the production of neurotoxic metabolites. Sixteen patients with chronic hepatitis C, free of psychiatric disorders and eligible for IFN-α treatment, were recruited. Depressive symptoms were measured using the Montgomery Asberg Depression Rating Scale (MADRS). Measurements of TRP, amino acids competing with TRP for entrance through the blood–brain barrier, KYN and kynurenic acid (KA), a neuroprotective metabolite, were performed using high-performance liquid chromatography. All assessments were carried out at baseline and 1, 2, 4, 8, 12 and 24 weeks after treatment was initiated. The MADRS score significantly increased during IFN-α treatment as did the KYN/TRP ratio, reflecting IDO activity, and the KYN/KA ratio, reflecting the neurotoxic challenge. The TRP/CAA (competing amino acids) ratio, reflecting TRP availability to the brain, did not significantly change during treatment. Total MADRS score was significantly associated over time with the KYN/KA ratio, but not with the TRP/CAA ratio. Although no support was found that IDO decreases TRP availability to the brain, this study does support a role for IDO activity in the pathophysiology of IFN-α-induced depressive symptoms, through its induction of neurotoxic KYN metabolites.
Animal models are used to decipher the pathophysiology of IFN-α-induced psychiatric complications in humans. However, the behavioral effects of IFN-α in rodents remain highly controversial. In contrast to homologous IFN-α, our recent study revealed that human IFN-α, which was used in many previous investigations, had no biological activity in mice. To evaluate the behavioral effects of homologous IFN-α in mice, adult C57BL/6J mice were treated with carrier-free murine IFN-α and tested on a number of behavioral paradigms. Surprisingly, contrary to previous reports, IFN-α treatment decreased the time spent immobile in the forced-swimming test after a single intraperitoneal injection at 2×106IU/kg, whereas general locomotor activity was not altered. The elevated plus-maze (EPM) test showed a trend toward an increased anxiety profile in IFN-α-treated mice. The tail-suspension and light dark exploration test revealed no difference between IFN-α-treated and control animals. Interestingly, neurochemical analysis revealed significantly increased concentrations of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA)/serotonin (5-HT) ratios following IFN-α treatment in selected brain regions. Thus, systemic murine IFN-α treatment increases swimming time in mice. Increased cerebral serotonin turnover as well as increased tryptophan concentrations, induced by IFN-α, implicates serotonergic neurotransmission in behavioral dysfunction caused by this innate immune mediator.
Immune activation induces a pro-inflammatory state, which enhances the tryptophan degradation into kynurenine (KYN). The involvement of kynurenines has been shown in patients with major depression. Here, the effects of anti-inflammatory medication and antidepressants on cytokines and tryptophan metabolite changes in blood culture with immune challenge [bacterial mimetic lipopolysaccharide (LPS)] were investigated.
A total of 21 depressed patients and 38 matched controls were recruited. Whole blood cultures were stimulated with LPS and drugs were added (celecoxib, venlafaxine, reboxetine, imipramine and fluoxetine). Cytokines and kynurenines were analysed.
After stimulation with LPS, the interferon-γ and interleukin (IL)-10 secretions were significantly higher in controls than in patients (p = 0.045, p = 0.032), respectively. Adding imipramine and celecoxib abolished the significance for IL-10. Challenge with LPS induced the kynurenine pathway in each group. Regarding the ratio KYNA/KYN, which indicated how much of KYN formed is further catabolised into the neuroprotective arm, the controls' blood cultures showed a significantly higher ratio (p = 0.045).
Stimulation with LPS induced increased production of pro-inflammatory and anti-inflammatory cytokines in both groups, but higher responses in controls. This lower production of cytokine responses in depressed patients indicates that their immune cells are in a refractory phase, induced by a pre-existing pro-inflammatory state. For kynurenines, the whole metabolism was enhanced by LPS; however, an imbalance to neuroprotective metabolites was observed just in control blood. A drug effect could only be shown for imipramine and celecoxib, which were beneficial in terms of re-balancing the immune function but not in re-balancing neuroactive metabolites.
Immune dysfunction, including monocytosis and increased blood levels of interleukin-1, interleukin-6 and tumour necrosis factor α has been observed during acute episodes of major depression. These peripheral immune processes may be accompanied by microglial activation in subregions of the anterior cingulate cortex where depression-associated alterations of glutamatergic neurotransmission have been described.
Microglial immunoreactivity of the N-methyl-D-aspartate (NMDA) glutamate receptor agonist quinolinic acid (QUIN) in the subgenual anterior cingulate cortex (sACC), anterior midcingulate cortex (aMCC) and pregenual anterior cingulate cortex (pACC) of 12 acutely depressed suicidal patients (major depressive disorder/MDD, n = 7; bipolar disorder/BD, n = 5) was analyzed using immunohistochemistry and compared with its expression in 10 healthy control subjects.
Depressed patients had a significantly increased density of QUIN-positive cells in the sACC (P = 0.003) and the aMCC (P = 0.015) compared to controls. In contrast, counts of QUIN-positive cells in the pACC did not differ between the groups (P = 0.558). Post-hoc tests showed that significant findings were attributed to MDD and were absent in BD.
These results add a novel link to the immune hypothesis of depression by providing evidence for an upregulation of microglial QUIN in brain regions known to be responsive to infusion of NMDA antagonists such as ketamine. Further work in this area could lead to a greater understanding of the pathophysiology of depressive disorders and pave the way for novel NMDA receptor therapies or immune-modulating strategies.
Cytokine-induced activation of indoleamine 2,3-dioxygenase (IDO) catabolizes L-tryptophan (TRP) into L-kynurenine (KYN), which is metabolized to quinolinic acid (QUIN) and kynurenic acid (KA). QUIN and KA are neuroactive and may contribute to the behavioral changes experienced by some patients during exposure to inflammatory stimuli such as interferon (IFN)-alpha. A relationship between depressive symptoms and peripheral blood TRP, KYN and KA during treatment with IFN-alpha has been described. However, whether peripheral blood changes in these IDO catabolites are manifest in the brain and whether they are related to central nervous system cytokine responses and/or behavior is unknown. Accordingly, TRP, KYN, QUIN and KA were measured in cerebrospinal fluid (CSF) and blood along with CSF concentrations of relevant cytokines, chemokines and soluble cytokine receptors in 27 patients with hepatitis C after approximately 12 weeks of either treatment with IFN-alpha (n=16) or no treatment (n=11). Depressive symptoms were assessed using the Montgomery-Asberg Depression Rating Scale. IFN-alpha significantly increased peripheral blood KYN, which was accompanied by marked increases in CSF KYN. Increased CSF KYN was in turn associated with significant increases in CSF QUIN and KA. Despite significant decreases in peripheral blood TRP, IFN-alpha had no effect on CSF TRP concentrations. Increases in CSF KYN and QUIN were correlated with increased CSF IFN-alpha, soluble tumor necrosis factor-alpha receptor 2 and monocyte chemoattractant protein-1 as well as increased depressive symptoms. In conclusion, peripheral administration of IFN-alpha activated IDO in concert with central cytokine responses, resulting in increased brain KYN and QUIN, which correlated with depressive symptoms.
In a little more than 10 years, the kynurenine metabolites of tryptophan have emerged from their former position as biochemical curiosities, to occupy a prominent position in research on the causes and treatment of several major CNS disorders. The pathway includes two compounds, quinolinic acid and kynurenic acid, which are remarkably specific in their pharmacological profiles: one is a selective agonist at receptors sensitive to NMDA, whereas the other is a selective antagonist at low concentrations at the strychnine-resistant glycine modulatory site associated with the NMDA receptor. It has been argued that these agents cannot be of physiological or pathological relevance because their normal extracellular concentrations, in the nanomolar range, are at least 3 orders of magnitude lower than those required to act at NMDA receptors. This is a facile argument, however, that ignores at least two possibilities. One is that both quinolinate and kynurenate may be present in very high concentrations locally at some sites in the brain that cannot be reflected in mean extracellular levels. Similar considerations apply to many neuroactive agents in the CNS. The fact that both compounds appear to be synthesised in, and thus emerge from, glial cells that are well recognised as enjoying a close physical and chemical relationship with some neurones in which the intercellular space may be severely restricted may support such a view. Certainly the realisation that NMDA receptors may not be fully saturated functionally with glycine would be consistent with the possibility that even quite low concentrations of kynurenate could maintain a partial antagonism at the glycine receptor. A second possibility is that there may be a subpopulation of NMDA receptors (or, indeed, for a quite different amino acid) that possesses a glycine modulatory site with a much lower sensitivity to glycine or higher sensitivity to kynurenate, making it more susceptible to fluctuations of endogenous kynurenine levels. Whatever the specific nature of their physiological roles, the presence of an endogenous selective agonist and antagonist acting at NMDA receptors must continue to present exciting possibilities for understanding the pathological basis of several CNS disorders as well as developing new therapeutic approaches. An imbalance in the production or removal of either of these substances would be expected to have profound implications for brain function, especially if that imbalance were present chronically.(ABSTRACT TRUNCATED AT 400 WORDS)
The existence of a number of classes of antidepressant drugs with diverse pharmacological effects would lead one to expect that antidepressant drugs acting through different pharmacological mechanisms should produce different behavioral effects. Animal behavioral tests used to screen antidepressant drugs do not, however, discriminate between drugs that selectively enhance serotonin or norepinephrine transmission. Several components of human depression are differently affected by drugs selectively interacting with either serotonin or norepinephrine transmission. The ideal animal model for detecting antidepressant drug effects should thus be sensitive to all antidepressant drugs and should also display multiple components that are sensitive to specific drug classes. The revised scoring of the forced swimming test corresponds to a behavioral test for antidepressant drugs that meet these criteria.
Depression commonly complicates treatment with the cytokine interferon alfa-2b. Laboratory animals pretreated with antidepressants have less severe depression-like symptoms after the administration of a cytokine. We sought to determine whether a similar strategy would be effective in humans.
In a double-blind study of 40 patients with malignant melanoma who were eligible for high-dose interferon alfa therapy, we randomly assigned 20 patients to receive the antidepressant paroxetine and 20 to receive placebo. The treatment was begun 2 weeks before the initiation of interferon alfa and continued for the first 12 weeks of interferon alfa therapy.
During the first 12 weeks of interferon alfa therapy, symptoms consistent with a diagnosis of major depression developed in 2 of 18 patients in the paroxetine group (11 percent) and 9 of 20 patients in the placebo group (45 percent) (relative risk, 0.24; 95 percent confidence interval, 0.08 to 0.93). Severe depression necessitated the discontinuation of interferon alfa before 12 weeks in 1 of the 20 patients in the paroxetine group (5 percent), as compared with 7 patients in the placebo group (35 percent) (relative risk, 0.14; 95 percent confidence interval, 0.05 to 0.85). The incidence of adverse events was similar in the two groups.
In patients with malignant melanoma, pretreatment with paroxetine appears to be an effective strategy for minimizing depression induced by interferon alfa.
We have previously shown that the risk of major depression in patients with malignant melanoma undergoing interferon-alpha (IFN-alpha) therapy can be reduced by pretreatment with the antidepressant, paroxetine. Using dimensional analyses, the present study assessed the expression and treatment responsiveness of specific clusters of neuropsychiatric symptoms over the first three months of IFN-alpha therapy. Forty patients with malignant melanoma eligible for IFN-alpha treatment were randomly assigned to receive either paroxetine or placebo in a double-blind design. Neuropsychiatric assessments were conducted at regular intervals during the first twelve weeks of IFN-alpha therapy and included the 21-item Hamilton Depression Rating Scale, the 14-item Hamilton Anxiety Rating Scale and the Neurotoxicity Rating Scale. Neurovegetative and somatic symptoms including anorexia, fatigue and pain appeared within two weeks of IFN-alpha therapy in a large proportion of patients. In contrast, symptoms of depressed mood, anxiety and cognitive dysfunction appeared later during IFN-alpha treatment and more specifically in patients who met DSM-IV criteria for major depression. Symptoms of depression, anxiety, cognitive dysfunction and pain were more responsive, whereas symptoms of fatigue and anorexia were less responsive, to paroxetine treatment. These data demonstrate distinct phenomenology and treatment responsiveness of symptom dimensions induced by IFN-alpha, and suggest that different mechanisms mediate the various behavioral manifestations of cytokine-induced "sickness behavior."
Current treatments for depression are inadequate for many individuals, and progress in understanding the neurobiology of depression is slow. Several promising hypotheses of depression and antidepressant action have been formulated recently. These hypotheses are based largely on dysregulation of the hypothalamic-pituitary-adrenal axis and hippocampus and implicate corticotropin-releasing factor, glucocorticoids, brain-derived neurotrophic factor, and CREB. Recent work has looked beyond hippocampus to other brain areas that are also likely involved. For example, nucleus accumbens, amygdala, and certain hypothalamic nuclei are critical in regulating motivation, eating, sleeping, energy level, circadian rhythm, and responses to rewarding and aversive stimuli, which are all abnormal in depressed patients. A neurobiologic understanding of depression also requires identification of the genes that make individuals vulnerable or resistant to the syndrome. These advances will fundamentally improve the treatment and prevention of depression.
We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.
Proinflammatory cytokines have the potential to activate the hypothalamo-pituitary-adrenocortical (HPA) axis, and HPA axis hyperactivity is also encountered in depression. Therefore, the induction of depressive symptoms by interferon-alpha (IFN-alpha) may be mediated by changes in the cytokine network and the HPA axis.
In 17 hepatitis C patients undergoing IFN-alpha treatment, depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS). In addition, serum cytokine concentrations were measured. Saliva was collected five times over the course of a day in order to assess daily average cortisol (DAC) and awakening response. Assessments were carried out at baseline and six later time points after starting treatment.
During treatment, the increases in the MADRS were significantly and positively correlated with soluble interleukin (IL)-2 receptor, tumor necrosis factor alpha (TNF-alpha), and IL-6. There were no significant associations between the DAC or cortisol awakening response with the MADRS score.
Results suggest a clear connection between IFN-alpha-induced depressive symptoms and cytokine concentrations, but not cortisol.
Indoleamine 2,3 dioxygenase (Ido1), the first and rate-limiting enzyme of the kynurenine pathway (KP), is a striatally-enriched gene with increased expression levels in the YAC128 mouse model of Huntington disease (HD). Our objective in this study was to delineate age-related KP alterations in this model. Three enzymes potentially catalyze the first step of the KP; Ido1 and Indoleamine 2,3 dioxygenase-2 (Ido2) were highly expressed in the striatum and Tryptophan 2,3 dioxygenase (Tdo2) in the cerebellum. During development, Ido1 mRNA expression is dynamically regulated and chronically upregulated in YAC128 mice. Kynurenine (Kyn) to tryptophan (Trp) ratio, a measure of activity in the first step of the KP, was elevated in YAC128 striatum, but no change in Tdo2 mRNA levels or Kyn to Trp ratio was detected in the cerebellum. Ido1 induction was coincident with Trp depletion at 3 months and Kyn accumulation at 12 months of age in striatum. Changes in downstream KP metabolites of YAC128 mice generally followed a biphasic pattern with neurotoxic metabolites reduced at 3 months and increased at 12 months of age. Striatally-specfic induction of Ido1 and downstream KP alterations suggest involvement in HD pathogenesis, and should be taken into account in future therapeutic developments for HD. This article is protected by copyright. All rights reserved.
Background
Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-α therapy.
One of the two core symptoms of depression as defined by the Diagnostic and statistical manual of mental disorders (DSM-IV) (American Psychiatric Association) is anhedonia, or a loss of interest or pleasure. Sucrose consumption has been described as a valid measure of sensitivity to reward. In the present set of studies, changes in sucrose consumption (three-bottle test using 1, 8 and 32% sucrose) were taken as a measure of the anhedonic effect of interferon-α (IFN-α). Sucrose tests were carried out following the i.p. administration (20 min pre-treatment time) of Recombinant Human Interferon-αA (rHIFN-α), 101, 102, 104 units(U) and Rat Interferon alpha (rRIFN-α), 1,10 and 100 IRU. Both types of IFN-α produced a decrease in sucrose consumption and drinking rate (DR) at the highest doses, with the greatest inhibition being at the lowest sucrose concentration (1%). Longer pre-treatment times with rHIFN-α (40 and 80 min prior to commencement of 1 h drinking test) resulted in insignificant effects. Significant hypothermia relative to vehicle-injected rats was observed following interferon administration in the 20 min pre-treatment condition, but showed no significant difference when compared to vehicle at 40 or 80 min. Overall these results confirm a depression-like behavioural syndrome (anhedonia) following administration of IFN-α.
Interferon-α (IFN-α)-induced "depressive-like" behavior is a major limitation for the treatment of hepatitis C virus (HCV), especially for patients with psychiatric disorders. Recently, serotonin 1A (5-HT(1A)) receptor and cellular apoptosis are involved in mechanism(s) contributing to depression. To gain insight into this mechanism(s), we used C57BL/6J mice to examine the impact of IFN-α on the modulation of 5-HT(1A) receptor and cellular apoptosis and their relationship. Our results showed that repeated administration of IFN-α (6 MIU/kg, s.c.) induced "depressive-like" behavior of mice in the forced swim test, tail suspension test and sucrose preference test. Besides, the depressive mice exhibited a notable downregulation of 5-HT(1A) receptor and upregulation of cleaved caspase-3 and Bax/Bcl-2 ratio. These changes could be blocked by the 5-HT(1A) receptor agonist 8-OH-DPAT (0.5 mg/kg, i.p., 30 min before IFN-α administration), but not by the standard antidepressant imipramine (10 mg/kg, i.p., 30 min before IFN-α administration) although both of them could ameliorate the depressive-like behavior of mice. These findings indicated that repeated injection with IFN-α provoked "depressive-like" behavior through cellular apoptosis, which could be ameliorated by the activation of 5-HT(1A) receptor.
Depressive disorders represent a major public health problem worldwide. The limitations of current antidepressant drugs have warranted on-going research to identify pharmacological agents and strategies that offer a greater therapeutic efficacy. The NMDA/L-arginine nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) cascade is an important signaling pathway that is also implicated in the regulation of depression. In animal models detecting antidepressant activity, distinct NO synthase inhibitors display antidepressant-like action. Therefore, the aim of current study was to evaluate whether pretreatment with L-arginine (precursor of NO) could counteract antidepressant-like effects of distinct antidepressant classes in the mouse forced swimming test (FST), and whether these drugs are able to modulate the nitric oxide synthesis in the brain. We found in the FST that pretreatment with L-arginine (500 mg/kg) counteracted the antidepressant-like effect of imipramine (IMI, 15 mg/kg) and venlafaxine (VENL, 6 mg/kg), but not the effects of bupropion (BUPR, 20mg/kg) or fluoxetine (FLX, 20mg/kg). Increasing the dose of L-Arg to 1000 mg/kg attenuated the antidepressant-like effects of BUPR, but did not modify the action of FLX. L-Arginine was devoid of any locomotor effects on the animals. The effect of antidepressants on brain NO metabolism paralleled their behavioral action in case of IMI and VENL which decreased the nitrite+nitrate concentration in the brain. BUPR and FLX did not have any effect on brain nitrite+nitrate concentration. These results support the idea that some antidepressants are able to inhibit nitric oxide synthesis in the brain, an effect which could be mechanistically related to the ability of L-arginine to counteract their antidepressant-like effects.
Adjuvant IFN-α treatment for patients with malignant melanoma is often complicated by depression. The influence of dosage, however, is unknown.
The authors sought to elucidate this dosage effect.
Using the Zung Self-Rating Depression Scale and the German Bf-S Self-Rating (Affectivity) Scale, the authors prospectively compared the frequency and severity of IFN-α-induced depressive symptoms between a group of 29 patients receiving low-dose and 17 patients getting high-dose induction therapy for 4 weeks.
Patients receiving high-dose induction treatment had significantly higher depression scores after 4 weeks, and significantly more patients in the high-dose group developed depression.
The authors concluded that frequency and severity of IFN-α-associated depression during melanoma treatment are dose-dependent.
The currently recommended therapy for chronic hepatitis C (HCV) is a combination of pegylated interferon-alpha (PEG-IFN alpha) and ribavirin. Psychiatric disorders, including depression, are frequent in HCV patients under therapy. We investigated the effect of the antiviral treatment on tryptophan (Trp) metabolism along both serotonin pathway (via 5-hydroxytryptophan, 5-HTP) and kynurenine (Kyn) pathway and on the onset of depressive symptoms in patients with HCV. The key enzyme of the Kyn pathway is indoleamine 2,3-dioxygenase (IDO), an intracellular haem protein enzyme expressed in several tissues. It was also investigated the influence of the therapy with PEG-IFN-alpha-2a or PEG-IFN-alpha-2b plus oral ribavirin and possible differences between genders. Free and total Trp, 5-hydroxytryptophan (5-HTP) and Kyn serum concentrations and the presence of depressive symptoms [Beck Depression Inventory (BDI) scores] were evaluated in 45 patients with HCV infection treated with PEG-IFN alpha-2a or -2b at four different times: baseline (before treatment), 1 and 6 months during therapy, and 3 months after the end of therapy. The concentration of serum total TRP (free+protein bound) as well as that of 5-HTP significantly decreased after 1 and 6 months of therapy, and then returned to baseline values 3 months after the end of therapy, while the levels of free TRP did not vary significantly during and after the therapy. On the contrary, the time course of Kyn markedly arose during treatment, paralleled by a significant increase of [Kyn/Trp]×10(3) ratio, an index used to measure IDO activity. No significant difference was detected between males and females neither between PEG-IFN-alpha-2a or -2b treatment. The BDI scores significantly increased during therapy, and returned to baseline values 3 months after the end of therapy. Our results support the hypothesis that the increased IDO-mediated tryptophan metabolism along the Kyn pathway, leading to plasma Trp depletion and a decline of serotonin pathway, concurs to the development of depressive symptoms observed in HCV patients undergoing IFN-alpha therapy.
Recent clinical trails reported that adjunctive cyclooxygenase (COX)-2 inhibition with celecoxib is beneficial in treating depression. However, another clinical study showed celecoxib did not have inhibitory effect of COX-2 in human brain when given at a therapeutic dose. Therefore, whether celecoxib is exerting its influence through COX inhibition or by some other mechanism remains unclear. The present study further investigated the effect of celecoxib on COX-2 expression, prostaglandin E(2) (PGE2, a major COX-2-mediated inflammatory mediator) concentration and the depressive-like behaviors in rats. Celecoxib was administrated by oral gavage to naive rats (16 mg/kg) or stressed rats (2, 8, 16 mg/kg, respectively) for 21 days, or to stressed rats for a single dose (16 mg/kg). The results showed that 21 days chronic unpredictable stress induced depressive-like behaviors and increased the COX-2 expression and PGE2 concentration in rat brain. Chronic treatments with celecoxib alleviated the depressive-like behavior and reversed the levels of COX-2 expression and PGE2 concentration in stressed rat in a dose-dependent manner. Celecoxib also improved the emotional state and decreased COX-2 expression and PGE2 concentration in naive rats. In addition, a single dose of celecoxib treatment reversed COX-2 expression and PGE2 concentration, but didn't alter the depressive-like behavior in stressed rat. These results suggest that COX-2 enzyme might play a key role in pathophysiology of depression. Furthermore, these data indicate that chronic celecoxib treatment reverse chronic unpredictable stress-induced depressive-like behavior might via reducing COX-2 enzyme in brain, and the selective COX-2 inhibitors could be developed as potential remedies for the management of depression.
Rats when forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture which can be readily identified. Immobility was reduced by various clinically effective antidepressant drugs at doses which otherwise decreased spontaneous motor activity in an open field. Antidepressants could thus be distinguished from psychostimulants which decreased immobility at doses which increased general activity. Anxiolytic compounds did not affect immobility whereas major tranquilisers enhanced it. Immobility was also reduced by electroconvulsive shock, REM sleep deprivation and "enrichment" of the environment. It was concluded that immobility reflects a state of lowered mood in the rat which is selectively sensitive to antidepressant treatments. Positive findings with atypical antidepressant drugs such as iprindole and mianserin suggest that the method may be capable of discovering new antidepressants hitherto undetectable with classical pharmacological tests.
Treatment with interferon (IFN) reduces viral replication and normalizes aminotransferase levels in a significant percentage of patients with non-A, non-B hepatitis or hepatitis C. Soluble immune activation markers were evaluated in patients with hepatitis.
Serum concentrations of soluble immune activation markers neopterin and beta 2-microglobulin (B2M) were compared to endogenous IFN-gamma levels in 17 patients with chronic hepatitis C before, during and after 9-months of treatment with IFN-alpha 2b.
Before therapy some patients had increased concentrations of the studied variables. During therapy neopterin and B2M concentrations further increased whereas IFN-gamma decreased. IFN-gamma and neopterin levels were correlated before but not during therapy. The correlations between neopterin and B2M were significant throughout the study.
The data indicate that IFN-gamma decreases during treatment and IFN-alpha 2b appears to enhance formation of neopterin and B2M.
In this study, we describe the lipoperoxidative effect of quinolinic acid (QUIN) in vitro. The formation of thiobarbituric acid reactive products (TBA-RP), an index of lipid peroxidation, was measured in rat brain homogenates after incubation at 37 degrees C for 30 min in the presence of QUIN and some structurally and metabolically related compounds such as Kynurenine, Kynurenic acid, Glutamate, Aspartate and Kainate. Concentrations of QUIN in the range of 20 to 80 microM increased lipid peroxidation in a concentration-dependent manner from about 15% to about 50%. Kynurenic acid, a compound metabollically related to QUIN that can block its neurotoxic actions in vivo, also inhibited completely the QUIN-induced TBA-RP formation in our system. Lipid fluorescent material, another index of lipid peroxidation was also found increased by 49% after incubation with 40 microM QUIN. It is concluded that lipid peroxidation may be a damaging process involved in the neurotoxicity of QUIN.
We investigated serum neopterin, tryptophan, and kynurenine concentrations in 23 HIV-1 seropositive patients (Walter Reed Stage 4-6). Ten patients presented with polyneuropathy and three with dementia, one of the patients with dementia also had polyneuropathy and dementia. We found significant associations between lower trytophan concentrations and neurologic/psychiatric symptoms. The negative correlation of tryptophan with kynurenine and neopterin concentrations indicates activity of indoleamine 2,3-dioxygenase (IDO) in patients. IDO can be induced by cytokines such as interferon-gamma and therefore low tryptophan levels may result from chronic immune stimulation in HIV-1 seropositives.
In the 35 years since the discovery of interferon, significant biological activity has been described for interferon-alpha (IFN alpha) in various cancers, particularly haematological malignancies such as hairy cell leukaemia and chronic myelogenous leukaemia. Except for localised therapy in bladder and ovarian cancer, activity against most solid tumours has been disappointing. Other notable exceptions include Kaposi's sarcoma, renal cell carcinoma and malignant melanoma, tumours known to be susceptible to immunological attack. More recently, broad spectrum antiviral activity has been demonstrated for both recombinant and naturally occurring IFN alpha. Hepatitis C is responsive to IFN alpha in about 40% of patients, but long term remissions are rare. In contrast, long term suppression of hepatitis B is common following IFN alpha therapy. Both diseases respond in a dose proportional fashion, with daily doses of 5 million units (MU) significantly more effective than lower doses. The mechanism of action in viral diseases involves the expression of unique antiviral proteins such as endonuclease and 2'-5'-oligoadenylate synthetase which enhance the destruction of viral RNA. General cellular protein synthesis is also inhibited, including cytochrome P450 enzymes. This forms the basis for potential drug interactions, with IFN alpha slowing the clearance of highly metabolised drugs such as theophylline. As an antitumour agent, the mechanism of action of IFN alpha is unclear, particularly in haematological cancers. In melanoma and renal cell carcinoma, antitumour effects may be mediated by augmented immune responses including activation of natural killer lymphocytes and enhanced expression of cell surface antigens (e.g. MHC I and II). Conversely, antibody formation to recombinant IFN alpha may result in a loss of activity. This has been observed in both renal cell cancer and hepatitis B and C. The elimination half-life of IFN alpha is short, 4 to 5 hours, but biological activity extends for 2 to 3 days after administration, which facilitates daily or thrice weekly administration. Clearance of IFN alpha is mediated by catabolism in the renal tubules; no intact drug is excreted in the urine. It is probable that the antiviral indications of IFN alpha will expand as the agent is more clearly recognised as a primary endogenous defence against various viral conditions.
Interferon-alpha decreases food intake and activity in mice and humans. The present study further explores parallels between effects of this protein in humans and mice, using a hybrid recombinant interferon-alpha A/D (INF-alpha A/D) that has antiviral and hepatic activity in mice. Measures of activity (open field), muscle strength (forelimb grip strength), and motor ability (swim posture and endurance with 0, 3, and 6% added weight) were examined in Balb/c mice injected with 1600 U/g of hybrid rhuIFN-alpha A/D daily for 5 days (n = 9) or with IFN vehicle (n = 11). Open field activity was significantly depressed in the group exposed to IFN. The number of times the nose dipped under the water when swimming with 3% added body weight was higher in the IFN-treated mice, while float time was decreased with 6% added weight. The IFN-treated mice were slower to adopt the new strategies necessary to swim with added weight. Depression of motor activity is a robust, general effect of IFN treatment observed in this as well as previously published studies. Together, these studies demonstrate activity decrements in two different strains of mice, two different activity measures, acute and chronic injections, and recombinant and nonrecombinant IFN preparations.
We investigated the depression induced by human interferons using the forced swimming test in mice. Intravenous (i.v.) administration of interferon-alpha s (natural interferon-alpha, recombinant interferon-alpha-2a and recombinant interferon-alpha-2b, 600-60000 IU/kg) increased the immobility time in the forced swimming test in a dose-dependent manner, but natural interferon-beta and recombinant interferon-gamma-1a did not affect the immobility time. The increase in the immobility time induced by recombinant interferon-alpha-2b peaked at 15 min after dosing. Administration of recombinant interferon-alpha-2b (6000 IU/kg, i.v.) once daily for 7 consecutive days increased the immobility time, but natural interferon-beta and recombinant interferon-gamma-la did not. Recombinant interferon-alpha-2b in combination with the anti-depressants imipramine (10 mg/kg, i.p.) and mianserin (20 mg/kg, i.p.) did not increase the immobility time. These results suggest that interferon-alpha has a greater potential for inducing depression than interferon-beta and -gamma, and that anti-depressants are effective against interferon-alpha-induced depression.
Depression-like behavior induced by YM643, a consensus interferon-alpha (IFN-alpha), was evaluated with the tail-suspension test in mice and compared with depression-like behavior induced by sumiferon, a natural IFN-alpha. To investigate the mechanism of IFN-alpha-induced depression-like behavior, the effects of the tricyclic antidepressant imipramine, the cyclooxygenase inhibitor indomethacin, the opioid receptor antagonist naloxone, and the selective corticotropin-releasing hormone receptor antagonist CP-154, 526 on IFN-alpha-induced depression-like behavior were evaluated. Intravenously injected YM643 (2 x 10(8)-2 x 10(9) U/kg) and sumiferon (2 x 10(6)-2 x 10(7) I.U./kg) dose-dependently increased immobility time. Repeated s.c. injection of either YM643 (6 x 10(6)-6 x 10(8) U/kg) or sumiferon (6 x 10(4)-6 x 10(6) I.U./kg) for 7 days also dose-dependently increased immobility time. After i.c.v. injection of either YM643 (2 x 10(6) U/mouse) or sumiferon (6 x 10(4) I.U./mouse), significant prolongation of immobility time also was observed. Pretreatment with imipramine (30 mg/kg s.c.) significantly reduced the YM643- or sumiferon-induced increases in immobility time. CP-154,526 (0.3-3 mg/kg s.c.) dose-dependently reduced YM643- or sumiferon-induced increases in immobility time with ID(50) values of 0.6 mg/kg against YM643 and 1.3 mg/kg against sumiferon. However, neither indomethacin (10 mg/kg s.c.) nor naloxone (3 mg/kg s.c.) had any effect on YM643- or sumiferon-induced increases in immobility time. These results suggest that IFN-alpha centrally induces depression-like behavior in mice that can be alleviated with imipramine. The results also suggest that activation of corticotropin-releasing hormone receptors is involved in IFN-alpha-induced depression-like behavior, but the prostaglandin and opioid systems do not participate in this process.
Objectives: We examined the immobility of the forced swimming test induced in an animal model by human interferon (IFN), which has often been reported to induce depression in clinical use.
In the present study, we examined the effects of human IFNs on results of the forced swimming test in rats.
Single intravenous (IV) administration of human IFN-alpha (6x10(4) IU/kg), but not of human IFN-beta or -gamma, significantly increased immobility time in the forced swimming test in rats. Repeated administration of human IFN-alpha (6x10(3) IU/kg) also significantly increased the immobility time. On the other hand, none of the rat IFNs (rat IFN-alpha, -beta and -gamma, 6x10(4) IU/kg, IV) changed the immobility time. Neither human IFNs nor rat IFNs changed the locomotor activity of rats.
These findings suggest that human IFN-alpha has a greater potential for inducing increase of the immobility in the rat forced swimming test than human IFN-beta and -gamma, and that the effect of human IFN-alpha might not be mediated through IFN-alpha/beta receptors.
One of the two core symptoms of depression as defined by the Diagnostic and statistical manual of mental disorders (DSM-IV) (American Psychiatric Association) is anhedonia, or a loss of interest or pleasure. Sucrose consumption has been described as a valid measure of sensitivity to reward. In the present set of studies, changes in sucrose consumption (three-bottle test using 1, 8 and 32% sucrose) were taken as a measure of the anhedonic effect of interferon-alpha (IFN-alpha). Sucrose tests were carried out following the i.p. administration (20 min pre-treatment time) of Recombinant Human Interferon-alphaA (rHIFN-alpha), 10(1), 10(2), 10(4) units(U) and Rat Interferon alpha (rRIFN-alpha), 1,10 and 100 IRU. Both types of IFN-alpha produced a decrease in sucrose consumption and drinking rate (DR) at the highest doses, with the greatest inhibition being at the lowest sucrose concentration (1%). Longer pre-treatment times with rHIFN-alpha (40 and 80 min prior to commencement of 1 h drinking test) resulted in insignificant effects. Significant hypothermia relative to vehicle-injected rats was observed following interferon administration in the 20 min pre-treatment condition, but showed no significant difference when compared to vehicle at 40 or 80 min. Overall these results confirm a depression-like behavioural syndrome (anhedonia) following administration of IFN-alpha.
There is now evidence that repeated administration of interferon-alpha (IFN-alpha) to patients with chronic active hepatitis and cancers induces depressive symptoms. There is also evidence that induction of the cytokine network modulates the serotonergic system and that major depression is related to activation of the cytokine network and disturbances in the serotonergic metabolism. The aims of this study were to examine the effects of IFN-alpha-based immunotherapy on the development of depressive symptoms in relation to its effects on plasma tryptophan and kynurenine and serum serotonin (5-HT). Eighteen patients affected by chronic active hepatitis C were treated with IFN-alpha (3-6 million units subcutaneously three to six times a week for 6 months) and had measurements of the previous parameters before starting immunotherapy and 2, 4, 16, and 24 weeks later. Severity of depression and anxiety were measured with the Montgomery-Asberg Depression Rating Scale (MADRS) and the Hamilton Rating Scale for Anxiety (HAM-A) scale, respectively. Immunochemotherapy with IFN-alpha (1) significantly increased the MADRS and HAM-A scores and serum kynurenine concentrations and (2) significantly reduced plasma tryptophan and serum 5-HT concentrations. IFN-alpha-based immunotherapy significantly increased the kynurenine per tryptophan quotient, which estimates the activity of indoleamine 2,3-dioxygenase, the major tryptophan-catabolizing enzyme, which is induced by IFNs. There are significant relationships between the IFN-alpha-induced changes in the MADRS score and serum kynurenine (positive) and 5-HT (negative) concentrations. Immunotherapy with IFN-alpha significantly increases the severity of depressive symptoms. The latter is related to changes in the serotonergic system, such as depletion of serum 5-HT and induction of the catabolism of tryptophan to kynurenine. It is suggested that the IFN-alpha-induced changes in the serotonergic turnover could play a role in the development of IFN-alpha-induced depressive symptoms.
Tryptophan (TRP) degradation into kynurenine (KYN) by the enzyme, indoleamine-2,3-dioxygenase, during immune activation may contribute to development of depressive symptoms during interferon (IFN)-alpha therapy.
Twenty-six patients with malignant melanoma were randomly assigned in double-blind fashion to receive either placebo or paroxetine, beginning 2 weeks before IFN-alpha treatment and continuing for the first 12 weeks of IFN-alpha therapy. At treatment initiation and at 2, 4, and 12 weeks of IFN-alpha treatment, measurements of TRP, KYN, and neopterin (a marker of immune activation), were obtained, along with structured assessments of depression, anxiety, and neurotoxicity.
Regardless of antidepressant treatment status, all patients exhibited significant increases in KYN, neopterin, and the KYN/TRP ratio during IFN-alpha therapy. Among antidepressant-free patients, patients who developed major depression exhibited significantly greater increases in KYN and neopterin concentrations and more prolonged decreases in TRP concentrations than did nondepressed, antidepressant-free patients. Moreover, in antidepressant-free patients, decreases in TRP correlated with depressive, anxious, and cognitive symptoms, but not neurovegetative or somatic symptoms. No correlations were found between clinical and biological variables in antidepressant-treated patients.
The results suggest that reduced TRP availability plays a role in IFN-alpha-induced depressive symptoms, and paroxetine, although not altering the KYN or neopterin response to IFN-alpha, attenuates the behavioral consequences of IFN-alpha-mediated TRP depletion.
Recombinant human interferon-alpha (IFN-alpha) induces depression, and neuroendocrine and neuroimmune activation, in a significant number of patients undergoing treatment for viral illnesses (e.g., hepatitis C), yet these effects have not been consistently reproduced in rodents. As such, we sought to determine the effects of acute or chronic IFN-alpha treatment on basic reward and immobility in the forced swim test (FST), neuroendocrine and neuroimmune activation, and monoamine turnover in brain. In the first experiment, male Wistar rats (N = 7/group) treated with human recombinant IFN-alpha (100,000 IU/kg, i.p.), as compared to saline, did not exhibit alterations to rate of sucrose pellet self-administration or total reinforcers obtained, corticosterone release, plasma IL-6 release, IL-1beta or IL-6 mRNA expression in hippocampus, or monoamine turnover in prefrontal cortex, striatum, nucleus accumbens, or amygdala. However, acute IFN-alpha decreased body weight and produced a trend toward reduced food consumption in the home cage 2 h after injection. In the second experiment, Wistar rats (N=4/group) were subjected to a chronic treatment regimen of saline or IFN-alpha (100,000 IU/kg, i.p.) once daily for 14 consecutive days. The data reveal that animals exposed to chronic IFN-alpha exhibited similar amounts of time immobile and similar latencies to primary immobility in the FST as compared to saline-treated controls. Chronic IFN-alpha did not induce corticosterone release, plasma TNF-alpha, or IL-6 release. Tissue monoamine analysis revealed that chronic IFN-alpha reduced DA levels in prefrontal cortex, and decreased 5-HT levels and increased 5-HT turnover in amygdala. In the third experiment, Wistar rats (N = 4/group) were exposed to either acute or chronic pegylated IFN-alpha (pegIFN-alpha: 3.25, 10 or 75 mg/kg, i.p.) at one of several time points from 1 h to 23 days. The data reveal that neither acute nor chronic pegIFN-alpha induced corticosterone release. Overall, the current report demonstrates that neither acute nor chronic IFN-alpha induced depressive-like behavior and neither IFN-alpha nor peg-IFN-alpha was capable of inducing neuroendocrine or neuroimmune activation. Despite the neurochemical alterations observed in the chronic treatment regimen, the data indicate that recombinant human IFN-alpha does not produce a robust model of depressive-like behavior in rodents.
Repeated administration of interferon-alpha (IFN-alpha) or pegylated IFN-alpha to patients with chronic hepatitis C viral infection induces a flu-like syndrome as well as neuropsychiatric side effects, which are well recognized, but poorly understood. Although pegylation appears to have improved viral response rates in patients with hepatitis C, there are still neurotoxicities associated with pegylated IFN-alpha therapy, in particular, depression, which can compromise and sometime prevent successful completion of antiviral treatment. This study assessed the effects of two forms of pegylated IFN-alpha [peginterferon-alfa-2a (PEG-2a) and peginterferon-alfa-2b (PEG-2b)] in rats in order to develop an animal model of IFN-induced "depression" (often described as sickness behavior) that can be used to more comprehensively investigate the neurochemical mechanisms of IFN-induced depression. Sixty male and female Lewis rats were randomly assigned to one of six treatment groups: (1) saline (SAL)+SAL (2) SAL+PEG-2a; (3) SAL+PEG-2b; (4) selective serotonin reuptake inhibitor (SSRI)+SAL, (5) SSRI+PEG-2a; (6) SSRI+PEG-2b. Rats were pretreated with intraperitoneal (i.p.) saline (0.9%) or 7.5mg/kg/day fluoxetine for 1 week, followed by 3 weeks of concurrent i.p. administration of 650 microg/wk of PEG-2a or PEG-2b. Using locomotor activity, the forced swim test, and weight gain as behavioral measures of sickness behavior, our data showed that Lewis rats did not develop an IFN-induced "depressive syndrome." Western blot analyses of brain and liver tissue indicated that signal transducer and activator of transcripton (STAT1) was not phosphorylated following IFN-alpha administration, suggesting that the pegylated compounds may not have bound type I IFN receptors in the rat. Collectively, our data suggest that Lewis rats are likely not a useful model to study IFN-induced depression.
Behavioural despair in rats: a new model sensitive to antidepressant treatments
- R D Porsolt
- G Anton
- N Blavet
- M Jalfre
R.D. Porsolt, G. Anton, N. Blavet, M. Jalfre, Behavioural despair in rats: a new
model sensitive to antidepressant treatments, Eur. J. Pharmacol. 47 (4) (1978)
379–391.
- E J Nestler
- M Barrot
- R J Dileone
- A J Eisch
- S J Gold
- L M Monteggia
E.J. Nestler, M. Barrot, R.J. DiLeone, A.J. Eisch, S.J. Gold, L.M. Monteggia,
Neurobiology of depression, Neuron 34 (1) (2002) 13-25.
Behavioural despair in rats: a new model sensitive to antidepressant treatments
- Porsolt
Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment
- Capuron
Interferon-alpha in malignant and viral diseases. A review
- Dorr