Inflammation modulates anxiety in an animal model of multiple sclerosis

Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, 44791 Bochum, Germany.
Behavioural brain research (Impact Factor: 3.03). 06/2011; 220(1):20-9. DOI: 10.1016/j.bbr.2011.01.018
Source: PubMed


Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by inflammation, but also degenerative changes. Besides neurological deficits, the rate of affective disorders such as depression and anxiety is at least six fold increased. Many aspects of MS can be mimicked in the animal model of myelin oligodendrocyte glycoprotein experimental autoimmune encephalomyelitis (MOG-EAE). Here we investigate behavioral changes in C57BL/6 mice suffering from mild MOG-EAE. In the later phase of the disease, mice were subjected to behavioral tests including the light-dark-box (LD Box), the acoustic startle response (SR) with a pre-pulse inhibition protocol as well as the learned helplessness (LH) paradigm. Behavioral data were correlated with the motor performance in an open field and rotarod test (RR). In the RR and open field, there was no significant difference in the motor performance between controls and mice suffering from mild MOG-EAE. Yet EAE mice displayed an increased anxiety-like behavior with a 23% reduction of the time spent in the bright compartment of the LD Box as well as an increased SR. In the LH paradigm, mice suffering from MOG-EAE were twice as much prone to depressive-like behavior. These changes correlate with an increase of hippocampal tissue tumor necrosis factor alpha levels and neuronal loss in the hippocampus. Modulation of monoaminergic transmission by chronic application of the antidepressant amitriptyline resulted in a decreased startle reaction and increased hippocampal norepinephrine levels. These data imply that chronic inflammation in the CNS may impact on emotional responses in rodent models of anxiety.

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    • "The sustained levels of inflammatory cytokines are associated with neurodegeneration and cognitive impairment[55]. Interestingly , it has been shown that the involvement of these cytokines in behavioural changes in EAE and in animal models of Alzheimer's, plus blocking the action of TNF-, reduces the cognitive deficit[45,56]. This information is consistent with the data from animals fed with cuprizone, since they have cognitive impairments and an increased concentration of[57]. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS). Further to the symptoms resulting from demyelination, new studies point to the involvement of neuroinflammation and white matter abnormalities in psychiatric disorders and neurodegenerative diseases. Cuprizone, a model of MS, produces consistent demyelination and elicits behavioural, morphological and inflammatory changes in animals that share some similarities with those observed in humans. In this study, we used the cuprizone model in Lewis Rats to evaluate clinical signs triggered by the demyelination process which could be comparable with the symptoms seen in white matter abnormalities in human beings. To induce the demyelination process, 0.6% cuprizone was added to the Lewis Rats' diet for four weeks. We proceeded with behavioural, morphological and immunological analyses. Animals fed with cuprizone exhibited behavioural changes: higher scores in the neurotoxicity test, reduced exploratory and locomotion behaviour, and also an increase of permanency in the closed arm of the elevated plus maze test, were observed. In these analyses, the animals showed motor coordination impairment and anxiety-like behaviour. Demyelination also triggered changes in discrimination of objects identified by an increase in the time spent close to a familiar object. These behavioural alterations were associated with a significant increase in the levels of TNF-alpha and corticosterone, consistent with the activation of microglia and astrocytes. Taken together, the results of this work show the cuprizone/Lewis rat model demyelination as an attractive paradigm for studying the correlation between white matter abnormalities and behaviour. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Apr 2015 · Behavioural brain research
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    • "In the present work, rats of the ''EAE'' group spent significantly more time in the center compared to the other tested groups. It may be suggested that the rats of the ''EAE'' group showed higher exploratory and lower anxiety behavior levels besides less emotion with respect to other groups, which is inconsistent with the findings of the previous studies (Peruga et al., 2011; Rodrigues et al., 2011). "
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    ABSTRACT: Experimental autoimmune encephalomyelitis (EAE) is a well-established animal model of multiple sclerosis. This study aimed to investigate the protective and therapeutic effects of Nigella sativa (N. sativa) seeds (2.8 g/kg body weight) in EAE-induced rats. EAE-induced animals were divided into: (1) EAE-induced animals (“EAE” group). (2) “N. sativa + EAE” group received a daily oral administration of N. sativa 2 weeks prior to EAE induction until the end of the experiment. (3) “EAE + N. sativa” group received a daily oral administration of N. sativa after the appearance of the first clinical signs until the end of the experiment. All animals were sacrificed at the 28th day post EAE-induction. Disease pathogenesis was monitored using a daily clinical scoring, body weight, open field test, histopathological and ultrastructural examination and determination of some oxidative stress parameters in the cortex and hippocampus. N. sativa ameliorated the clinical signs and suppressed inflammation observed in EAE-induced rats. In addition, N. sativa enhanced remyelination in the hippocampus. However, protection of rats with N. sativa administered 2 weeks prior to EAE induction and its continuation until the end of the experiment resulted in a significant increase in the cortical lipid peroxide level with reference to control and “EAE” rats. In conclusion, N. sativa seeds could be used as a protective agent or an adjunct treatment for EAE even when the treatment started after the appearance of the first clinical signs. However, the dose and duration of N. sativa must be taken into consideration to avoid its probable pro-oxidant effect.
    Full-text · Article · Sep 2014
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    • "Genetic risk factors have only been partially identified, implying HLA- DR alleles to be associated with increased risk of depression in MS (Schiffer et al. 1988) and ApoE ε2 alleles as having a protective effect (Julian et al. 2009). In a rodent model of MS, higher hippocampal TNF-α levels positively correlated with depressive symptoms (Peruga et al. 2011), while in another study peripheral TNF-α and interferon-γ (IFN-γ) mRNA correlated with the severity of depressive symptoms during an acute exacerbation in MS patients (Kahl et al. 2002). Structural neuroimaging techniques provide further evidence regarding the pathophysiology of depression and anxiety in MS, demonstrating the risk of depression to be associated with a higher lesion load in the medial inferior prefrontal cortex and the anterior temporal lobe of the dominant hemisphere, as well as with atrophy of the dominant anterior temporal lobe (Pujol et al. 1997; Bakshi et al. 2000; Feinstein et al. 2004). "
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    ABSTRACT: Laquinimod is a novel oral immunomodulatory drug for the treatment of multiple sclerosis (MS). Considering the frequent co-morbidity of MS with anxiety and depression, we sought to assess the antidepressant and anxiolytic effects of laquinimod in mouse models. Laquinimod (0.5-25 mg/kg), fluoxetine (10 mg/kg) or vehicle were administered for 4-14 days to adult Balb/c mice, followed by behavioral tests and brain BDNF analysis. Following a 4-day administration of laquinimod (5 and 25 mg/kg), an increase in motivated behavior was observed in the forced swim test (p < 0.01 vs. controls). In the open field test, laquinimod (0.5-5 mg/kg), but not fluoxetine, significantly increased motility (p < 0.05), whereas both decreased anxiety behavior (p < 0.01), evident only for laquinimod (5 mg/kg) in the elevated plus maze (p < 0.05). Following 7 days of administration, both drugs decreased anxiety behavior in the elevated plus maze and marble burying tests (p < 0.001 and p < 0.02, respectively). After 14 days, only laquinimod (5 mg/kg) demonstrated anxiolytic efficacy in the open field test (p < 0.05), with evidence of increased BDNF in response to 5-25 mg/kg in the hippocampus, but not frontal cortex (p < 0.05). In conclusion, laquinimod may possess anxiolytic and antidepressant effects, possibly associated with hippocampal BDNF increase, offering promise for MS patients suffering from psychiatric co-morbidity.
    Full-text · Article · Jul 2014 · Journal of Molecular Neuroscience
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