Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice

Adi Gross, Felix Benninger, Ravit Madar, Tomer Illouz, Kathleen Griffioen, Israel Steiner, Daniel Offen, Eitan Okun

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Objective: Epilepsy affects 60 million people worldwide. Despite the development of antiepileptic drugs, up to 35% of patients are drug refractory with uncontrollable seizures. Toll-like receptors (TLRs) are central components of the nonspecific innate inflammatory response. Because TLR3 was recently implicated in neuronal plasticity, we hypothesized that it may contribute to the development of epilepsy after status epilepticus (SE). Methods: To test the involvement of TLR3 in epileptogenesis, we used the pilocarpine model for SE in TLR3-deficient mice and their respective wild-type controls. In this model, a single SE event leads to spontaneous recurrent seizures (SRS). Two weeks after SE, mice were implanted with wireless electroencephalography (EEG) transmitters for up to 1 month. The impact of TLR3 deficiency on SE was assessed using separate cohorts of mice regarding EEG activity, seizure progression, hippocampal microglial distribution, and expression of the proinflammatory cytokines tumor necrosis factor (TNF)α and interferon (IFN)β. Results: Our data indicate that TLR3 deficiency reduced SRS, microglial activation, and the levels of the proinflammatory cytokines TNFα and IFNβ, and increased survival following SE. Significance: This study reveals novel insights into the pathophysiology of epilepsy and the contribution of TLR3 to disease progression. Our results identify the TLR3 pathway as a potential future therapeutic target in SE.

Original languageEnglish
Pages (from-to)586-596
Number of pages11
JournalEpilepsia
Volume58
Issue number4
Early online date6 Feb 2017
DOIs
StatePublished - 1 Apr 2017

Bibliographical note

Publisher Copyright:
Wiley Periodicals, Inc. © 2017 International League Against Epilepsy

Keywords

  • Epileptogenesis
  • Microglia
  • Neuroinflammation
  • SE
  • TLR3
  • Toll-like receptors

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