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

Abstract

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.

mGlu3 receptor regulates microglial cell reactivity in neonatal rats

“…A large body of evidence shows that mGlu5 receptor activation drives microglia toward an anti-inflammatory phenotype [ 20 , 55 – 58 ] and restrains microglia-driven neuroinflammation in models of temporal lobe epilepsy [ 59 ], Parkinson’s disease [ 60 ], subarachnoid hemorrhage [ 61 ], and traumatic brain injury [ 62 ]. Indeed, a reduction of mGlu5 receptor expression in LPD/IL-1β microglia has been observed at P4 and in a lower extent at P7 and P10.…”

Facets of Theiler’s Murine Encephalomyelitis Virus-Induced Diseases: An Update

“…With respect to viral-induced seizures and epilepsy, the discovery and characterization of new therapeutics to prevent, ameliorate, and inhibit seizures/epilepsy are in urgent need because seizures are often refractory to current treatments and associated with comorbidities such as psychiatric disorders and cognitive decline [90]. Besides the inflammatory pathways as targets for intervention, the recent finding that positive modulation of the mGluR5-reduced seizures and the percent of microglia and macrophages producing TNF-α in TMEV-infected C57BL/6 mice [255] indicates that mGluR5 may represent a potential therapeutic target. Holistic approaches, such as global gene expression analyses comparing different mouse strains and the use of congenic mouse models, will help to identify targets responsible for persistent infection and disease susceptibility.…”

Astrocyte Glutamate Uptake and Signaling as Novel Targets for Antiepileptogenic Therapy

“…mGluR5 expression in reactive astrocytes is persistently upregulated following electrically induced SE in a kindling model and in TLE (34). Selective positive modulation of mGluR5 in the Theiler's murine encephalomyelitis virus (TMEV)induced model of epilepsy attenuates seizures (41). Additionally, selectively knocking out astrocytic mGluR5 signaling during epilepsy slows glutamate clearance through glutamate transporters, suggesting that mGluR5 plays an important function in regulating these transporters in epileptogenesis (42).…”