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

Tyler J. Hanak, Jane E. Libbey, Daniel J. Doty, Jordan T. Sim, Ana Beatriz DePaula-Silva, Robert S Fujinami

Research output: Contribution to journalArticle

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.

LanguageEnglish (US)
Pages194-204
Number of pages11
JournalExperimental Neurology
Volume311
DOIs
StatePublished - Jan 1 2019

Fingerprint

Metabotropic Glutamate 5 Receptor
Temporal Lobe Epilepsy
Microglia
Theilovirus
Seizures
Tumor Necrosis Factor-alpha
Macrophages
Viruses
Epilepsy
Brain
Interleukin-6
Viral Encephalitis
Cytokines
Viral Antigens
G-Protein-Coupled Receptors
Pharmacology

Keywords

  • Epilepsy
  • Metabotropic glutamate receptor 5
  • Picornavirus
  • Seizures
  • Temporal lobe epilepsy
  • Theiler's murine encephalomyelitis virus
  • Tumor necrosis factor α
  • Viral encephalitis
  • VU0360172

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Cite this

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. / Hanak, Tyler J.; Libbey, Jane E.; Doty, Daniel J.; Sim, Jordan T.; DePaula-Silva, Ana Beatriz; Fujinami, Robert S.

In: Experimental Neurology, Vol. 311, 01.01.2019, p. 194-204.

Research output: Contribution to journalArticle

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