Hippocampal TNFα Signaling Contributes to Seizure Generation in an Infection-Induced Mouse Model of Limbic Epilepsy.

Autor:	Patel DC; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112., Wallis G; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112., Dahle EJ; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112.; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT 84112., McElroy PB; Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045., Thomson KE; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT 84112., Tesi RJ; INmune Bio, Seattle, WA 98117., Szymkowski DE; Xencor Inc., Monrovia, CA 91016., West PJ; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112.; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT 84112., Smeal RM; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112.; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT 84112., Patel M; Department of Pharmaceutical Sciences, University of Colorado, Aurora, CO 80045., Fujinami RS; Department of Pathology, University of Utah, Salt Lake City, UT 84112., White HS; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112.; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT 84112., Wilcox KS; Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT 84112.; Anticonvulsant Drug Development Program, University of Utah, Salt Lake City, UT 84112.
Jazyk:	angličtina
Zdroj:	ENeuro [eNeuro] 2017 May 09; Vol. 4 (2). Date of Electronic Publication: 2017 May 09 (Print Publication: 2017).
DOI:	10.1523/ENEURO.0105-17.2017
Abstrakt:	Central nervous system infection can induce epilepsy that is often refractory to established antiseizure drugs. Previous studies in the Theiler's murine encephalomyelitis virus (TMEV)-induced mouse model of limbic epilepsy have demonstrated the importance of inflammation, especially that mediated by tumor necrosis factor-α (TNFα), in the development of acute seizures. TNFα modulates glutamate receptor trafficking via TNF receptor 1 (TNFR1) to cause increased excitatory synaptic transmission. Therefore, we hypothesized that an increase in TNFα signaling after TMEV infection might contribute to acute seizures. We found a significant increase in both mRNA and protein levels of TNFα and the protein expression ratio of TNF receptors (TNFR1:TNFR2) in the hippocampus, a brain region most likely involved in seizure initiation, after TMEV infection, which suggests that TNFα signaling, predominantly through TNFR1, may contribute to limbic hyperexcitability. An increase in hippocampal cell-surface glutamate receptor expression was also observed during acute seizures. Although pharmacological inhibition of TNFR1-mediated signaling had no effect on acute seizures, several lines of genetically modified animals deficient in either TNFα or TNFRs had robust changes in seizure incidence and severity after TMEV infection. TNFR2 -/- mice were highly susceptible to developing acute seizures, suggesting that TNFR2-mediated signaling may provide beneficial effects during the acute seizure period. Taken together, the present results suggest that inflammation in the hippocampus, caused predominantly by TNFα signaling, contributes to hyperexcitability and acute seizures after TMEV infection. Pharmacotherapies designed to suppress TNFR1-mediated or augment TNFR2-mediated effects of TNFα may provide antiseizure and disease-modifying effects after central nervous system infection. Competing Interests: Authors do not have any conflicts of interest.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu