Astrocytic TNFα regulates the behavioral response to antidepressants.

Recent studies have suggested that cytokines, and in particular tumor necrosis factor alpha (TNFα), have a role in modulating antidepressant efficacy. To directly test this idea, we compared the response of TNFα(-/-) mice and astrocyte-specific TNFα(-/-) mice to the antidepressants fluoxetine and desipramine. Using standard behavior models for measuring antidepressant efficacy, the forced swim test (FST) and tail suspension test (TST), we determined that TNFα(-/-) mice were essentially normal in basal behavior in the FST and TST. However, TNFα(-/-) mice showed no behavioral response to a standard dose of chronic antidepressant treatment, in sharp contrast to wildtype mice. Similar results were seen with acute antidepressant treatment, but TNFα(-/-) mice did respond to a very high-dose acute antidepressant treatment. We also assessed in vitro and in vivo effects of fluoxetine on TNFα expression. Glia responded to serotonin in vitro and fluoxetine in vivo by upregulating TNFα mRNA. Consistent with this source of TNFα, mice with an astrocyte-specific deletion of TNFα also did not respond to standard chronic antidepressant treatment. These data suggest that astrocytic TNFα is important to the sensitivity of the behavioral response to administration of antidepressants.

An adaptive role of TNFα in the regulation of striatal synapses.

Elevation of inflammatory cytokines in the striatum precedes symptoms in a number of motor dysfunctions, but it is unclear whether this is part of the disease process or an adaptive response to the pathology. In pyramidal cells, TNFα drives the insertion of AMPA-type glutamate receptors into synapses, and contributes to the homeostatic regulation of circuit activity in the developing neocortex. Here we demonstrate that in the mouse dorsolateral striatum, TNFα drives the internalization of AMPARs and reduces corticostriatal synaptic strength, dephosphorylates DARPP-32 and GluA1, and results in a preferential removal of Ca(2+)-permeable AMPARs. Striatal TNFα signaling appears to be adaptive in nature, as TNFα is upregulated in response to the prolonged blockade of D2 dopamine receptors and is necessary to reduce the expression of extrapyramidal symptoms induced by chronic haloperidol treatment. These data indicate that TNFα is a regulator of glutamatergic synaptic strength in the adult striatum in a manner distinct from its regulation of synapses on pyramidal cells and mediates an adaptive response during pathological conditions.

Antioxidant potential of Minocycline in Japanese Encephalitis Virus infection in murine neuroblastoma cells: correlation with membrane fluidity and cell death.

Minocycline is neuroprotective in animal models of a number of acute CNS injuries, neurodegenerative diseases and CNS infection. While anti-inflammatory and anti-apoptotic effects of Minocycline have been characterized, the molecular basis for the neuroprotective effects of Minocycline remains unclear. We report here that Minocycline and two classical antioxidant compounds inhibit the Japanese Encephalitis Virus (JEV)-induced free radical generation in mouse neuroblastoma. In cultures of Neuro2a (N2a) cells infected with JEV for up to 24h, the number of cells undergoing cell death was also reduced by Minocycline (20 microM). JEV infection resulted in increased oxidative stress, as revealed by an increase in the fluorescence intensity for 5-(and-6)-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA), a reactive oxygen species (ROS) indicator. Minocycline at 20 microM inhibited this ROS production. Cells were moderately protected from JEV-induced death by diphenyleneiodonium (DPI), an inhibitor of flavon-containing enzyme inhibitor, whereas common antioxidants such as N-acetyl-cysteine (NAC) turned out to be ineffective. Direct antioxidant property of Minocycline and reference antioxidant compounds is evaluated by LDH assay, ROS measurement and mitochondrial membrane potential measurement. Our findings suggest that Minocycline reduces the neuronal damage seen in JEV infection in neuronal cell culture models at least in part through inhibition of oxidative stress.

Japanese encephalitis virus infection decrease endogenous IL-10 production: correlation with microglial activation and neuronal death.

The anti-inflammatory cytokine interleukin (IL)-10 is synthesized in the central nervous system (CNS) and acts to limit clinical symptoms of stroke, multiple sclerosis, Alzheimer's disease, meningitis, and the behavioral changes that occur during bacterial infections. Expression of IL-10 is critical during the course of most major diseases in the CNS and promotes survival of neurons and all glial cells in the brain by blocking the effects of proinflammatory cytokines and by promoting expression of cell survival signals. In order to assess functional importance of this cytokine in viral encephalitis we have exploited an experimental model of Japanese encephalitis (JE). We report for the first time that in Japanese encephalitis, there is a progressive decline in level of IL-10. The extent of progressive decrease in IL-10 level following viral infection is inversely proportional to the increase in the level of proinflammatory cytokines as well as negative consequences that follows viral infection.

Induction of IP-10 (CXCL10) in astrocytes following Japanese encephalitis.

Chemokines and their receptors are important elements for the selective attraction and activation of various subsets of leukocytes. Interferon-gamma inducible protein (IP-10 or CXCL-10) is a potent chemoattractant and has been suggested to enhance the severity of virus infection and neuronal injury. In order to assess functional importance of this chemokine in viral encephalitis, we have exploited an experimental model of Japanese encephalitis. We report for the first time that in Japanese encephalitis, astrocytes are the predominant source of IP-10. A progressive increase in IP-10 induction following viral infection is concomitant with the increase in IFN-gamma a known inducer of IP-10. However, this increase in IFN-gamma level is not sufficient to confer protection as animals eventually succumb to the infection.