Amitriptyline Suppresses Neuroinflammation-dependent Interleukin-10-p38 Mitogen-activated Protein Kinase-Heme Oxygenase-1 Signaling Pathway in Chronic Morphine-infused Rats
ABSTRACT This study explores the underlying mechanism of the antiinflammatory effect of amitriptyline in chronic morphine-infused rats.
Male Wistar rats were implanted with two intrathecal catheters. One catheter was for the continuous infusion of saline, amitriptyline (15 microg/h), morphine (15 microg/h), p38 mitogen-activated protein kinase inhibitor SB203580 (0.5 microg/h), morphine plus amitriptyline, or morphine plus amitriptyline plus SB203580 for 5 days. The other catheter was used for daily intrathecal injection of anti-interleukin-10 (IL-10) antibody or heme oxygenase-1 inhibitor zinc protoporphyrin for 5 days.
Amitriptyline/morphine coinfusion upregulated IL-10 protein expression in microglia; this was not observed in morphine-infused rats. Anti-IL-10 antibody effectively neutralized the amitriptyline-induced IL-10 expression in chronic morphine-infused rats. In addition, coinfusion of amitriptyline restored the antinociceptive effect of morphine (a 4.8-fold right-shift of the morphine dose-response curve compared to a 77.8-fold right-shift in its absence), and the injection of anti-IL-10 antibody or coinfusion of SB203580 partially reversed the effect of amitriptyline on the antinociceptive effect of morphine in morphine-infused rats (a 17.9-fold and 15.1-fold right-shift in morphine dose-response curves). Anti-IL-10 antibody and SB203580 significantly inhibited the amitriptyline-induced p38 mitogen-activated protein kinase and heme oxygenase-1 expression and the associated antiinflammatory effect of amitriptyline. Daily injection of zinc protoporphyrin also demonstrated that it reverses the effect of amitriptyline in morphine's antinociception and antiinflammation in chronic morphine-infused rats.
These results suggest that the antiinflammatory effect of amitriptyline on morphine tolerance, probably acting by increasing IL-10 expression, is mediated by p38 mitogen-activated protein kinase heme oxygenase-1 signal transduction cascade.
- SourceAvailable from: Elvira Valera
[Show abstract] [Hide abstract]
- "Interestingly, levels of other anti-inflammatory cytokines, such as IL-1ra and IL-13, were increased in the MBP1-ha-syn tg mice when compared to non-tg controls, suggesting that antiinflammatory compensatory mechanisms might be at play. Antidepressants, acting on serotonin, norepinephrine and dopamine receptors, are anti-inflammatory against proinflammatory cytokine processes, specifically by regulating IFN-c (Yuan et al., 2012), IL-10 (Song et al., 2009; Tai et al., 2009), TNF-a (Sadeghi et al., 2011; Song et al., 2009) and IL-6 (Liu et al., 2011). Fluoxetine protects neurons against microglia-mediated neurotoxicity in vitro, by inhibiting microglial NF-jB activation and the consequent decrease in the production of proinflammatory factors (Zhang et al., 2012). "
ABSTRACT: Multiple system atrophy (MSA) is a neurodegenerative disease characterized by the pathological accumulation of alpha-synuclein (α-syn) within oligodendroglial cells. This accumulation is accompanied by neuroinflammation with astrogliosis and microgliosis, that leads to neuronal death and subsequent parkinsonism and dysautonomia. Antidepressants have been explored as neuroprotective agents as they normalize neurotrophic factor levels, increase neurogenesis and reduce neurodegeneration, but their anti-inflammatory properties have not been fully characterized. We analyzed the anti-inflammatory profiles of three different antidepressants (fluoxetine, olanzapine and amitriptyline) in the MBP1-hα-syn transgenic (tg) mouse model of MSA. We observed that antidepressant treatment decreased the number of α-syn-positive cells in the basal ganglia of 11-month-old tg animals. This reduction was accompanied with a similar decrease in the colocalization of α-syn with astrocyte markers in this brain structure. Consistent with these results, antidepressants reduced astrogliosis in the hippocampus and basal ganglia of the MBP1-hα-syn tg mice, and modulated the expression levels of key cytokines that were dysregulated in the tg mouse model, such as IL-1β. In vitro experiments in the astroglial cell line C6 confirmed that antidepressants inhibited NF-κB translocation to the nucleus and reduced IL-1β protein levels. We conclude that the anti-inflammatory properties of antidepressants in the MBP1-hα-syn tg mouse model of MSA might be related to their ability to inhibit α-syn propagation from oligodendrocytes to astroglia and to regulate transcription factors involved in cytokine expression. Our results suggest that antidepressants might be of interest as anti-inflammatory and α-syn-reducing agents for MSA and other α-synucleinopathies. GLIA 2013.Glia 02/2014; 62(2). DOI:10.1002/glia.22610 · 6.03 Impact Factor
[Show abstract] [Hide abstract]
- "In the case of fluoxetine and amitriptyline , Yaron et al. (1999) showed that these drugs inhibit the release of nitric oxide and prostaglandin E2 in synovial cells. Moreover, Tai et al. (2009) observed that amitriptyline inhibits the expression of proinflammatory cytokines through increased IL-10, corroborating the concept that these TCAs may act as inflammatory suppressors (Xia et al. 1996; Yaron et al. 1999; Achar et al. 2003; Tai et al. 2009). However, studies exist reporting possible cytotoxic effects of amitriptyline (Viola et al. 2000; Kitagawa et al. 2006; Lirk et al. 2006; Moreno-Fernandez et al. 2008; Cordero et al. 2009), manifested through lipid peroxidation, decreased levels of cytochrome C and other alterations that indicate mitochondrial injury, suggesting that amitriptyline induces oxidative stress, which is known to increase the intensity of the inflammatory response. "
ABSTRACT: Infravesical obstruction (IVO) secondary to benign prostatic hypertrophy can affect up to 50% of men over 50 years old and may cause serious and irreversible alterations throughout the urinary tract, especially in the bladder. Therapeutic approaches are currently limited. Amitriptyline has recently been described as an analgesic, anti-inflammatory and myorelaxant in some experimental models. The objective of this study was to investigate the effects of amitriptyline hydrochloride on the process of fibrosis in a bladder outlet obstruction model in rats. Male Wistar rats were subjected to IVO and studied at intervals of 1 and 14 days postprocedure. The rats were randomly divided into five groups: sham, IVO1-T, IVO1-NT, IVO14-T and IVO14-NT. Bladder tissue was processed for histopathology, immunohistochemistry and RT-PCR. The IVO14 groups presented bladder fibrosis, smooth muscle cell hypertrophy and bladder wall thickening. The IVO14-T group demonstrated a higher intensity of fibrosis, higher macrophage infiltration rate and higher gene expression of Transforming growth factor (TGF) Tgf-β1. Thus this data shows that in this experimental mode amitriptyline had an amplifying effect on the process of fibrosis as a whole.International Journal of Experimental Pathology 05/2012; 93(3):218-24. DOI:10.1111/j.1365-2613.2012.00813.x · 2.05 Impact Factor
[Show abstract] [Hide abstract]
- "to be associated with an enhancement of heme oxygenase - 1 ( HO - 1 ) expression ( Kim et al , 2008 ; Shin et al , 2009 ; Tai et al , 2009 ) . HO is a rate - limiting enzyme that catalyzes the conversion of heme to equimolar amounts of CO , iron , and biliverdin ( Abraham and Kappas , 2008 ) . "
ABSTRACT: Accumulating evidence suggests that the pathophysiology of depression might be associated with neuroinflammation, which could be attenuated by pharmacological treatment for depression. Omega-3 polyunsaturated fatty acids (PUFAs) are anti-inflammatory and exert antidepressant effects. The aim of this study was to identify the molecular mechanisms through which docosahexaenoic acid (DHA), the main omega-3 PUFA in the brain, modulates oxidative reactions and inflammatory cytokine production in microglial and neuronal cells. The results of this study showed that DHA reduced expressions of tumor necrosis factor-α, interleukin-6, nitric oxide synthase, and cyclo-oxygenase-2, induced by interferon-γ, and induced upregulation of heme oxygenase-1 (HO-1) in BV-2 microglia. The inhibitory effect of DHA on nitric oxide production was abolished by HO-1 inhibitor zinc protoporphyrin IX. In addition, DHA caused AKT and ERK activation in a time-dependent manner, and the DHA-induced HO-1 upregulation could be attenuated by PI-3 kinase/AKT and MEK/ERK inhibitors. DHA also increased IKKα/β phosphorylation, IκBα phosphorylation, and IκBα degradation, whereas both nuclear factor-κB and IκB protease inhibitors could inhibit DHA-induced HO-1 expressions. The other major n-3 PUFA, eicosapentaenoic acid, showed similar effects of DHA on inflammation and HO-1 in repeated key experiments. In connecting with inflammation hypothesis of depression and clinical studies supporting the antidepressant effects of omega-3 PUFAs, this study provides a novel implication of the antidepressant mechanisms of DHA.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2010; 35(11):2238-48. DOI:10.1038/npp.2010.98 · 7.83 Impact Factor