Positive modulation of mGluR5 attenuates seizures and reduces TNF-α+ macrophages and microglia in the brain in a murine model of virus-induced temporal lobe epilepsy.

Viral encephalitis markedly increases the risk for the development of epilepsy. The Theiler's murine encephalomyelitis virus (TMEV)-induced model of seizures/epilepsy is a murine model of both viral-induced seizures/epilepsy and human Temporal Lobe Epilepsy. The inflammatory cytokines interleukin (IL)-6 and tumor necrosis factor (TNF)-α have been shown to play a role in seizure development in the TMEV-induced model of seizures/epilepsy, and infiltrating macrophages along with microglia have been shown to be major producers of these cytokines. The metabotropic glutamate receptor 5 (mGluR5) is a G-protein coupled receptor that has been shown to reduce IL-6 and TNF-α and to provide neuroprotection in other disease models. Therefore, we hypothesized that stimulation of mGluR5 would not only reduce seizures but attenuate IL-6 and TNF-α production in microglia and macrophages in the TMEV model. We found that pharmacological stimulation of mGluR5 with the selective positive allosteric modulator VU0360172 not only reduced acute seizure outcomes, but also reduced the percent of microglia and macrophages producing TNF-α 3 days post infection. Furthermore, treatment with VU0360172 did not alter the level of viral antigen, compared to controls, showing that this treatment does not compromise viral clearance. These results establish that mGluR5 may represent a therapeutic target in the TMEV-induced model of seizures/epilepsy.

The effects of diet on the severity of central nervous system disease: One part of lab-to-lab variability.

OBJECTIVE: Many things can impact the reproducibility of results from laboratory to laboratory. For example, food from various sources can vary markedly in composition. We examined the effects of two different food sources, the Teklad Global Soy Protein-Free Extruded Rodent Diet (irradiated diet) and the Teklad Sterilizable Rodent Diet (autoclaved diet), on central nervous system disease. METHODS: Three preclinical models for human disease: Two different experimental autoimmune encephalomyelitis models (multiple sclerosis) and the Theiler's murine encephalomyelitis virus-induced seizure model (epilepsy), were examined for the effects of two different food sources on disease. RESULTS: We found that mice fed the irradiated diet had more severe clinical disease and enhanced seizures compared with animals provided the autoclaved diet in both experimental autoimmune encephalomyelitis models examined and in the Theiler's murine encephalomyelitis virus-induced seizure model, respectively. CONCLUSIONS: Therefore, just altering the source of food (lab chow) can have marked effects on disease severity and outcome.