Blockade of the IL-1R1/TLR4 pathway mediates disease-modification therapeutic effects in a model of acquired epilepsy

Neurobiol Dis. 2017 Mar;99:12-23. doi: 10.1016/j.nbd.2016.12.007. Epub 2016 Dec 9.

Abstract

We recently discovered that forebrain activation of the IL-1 receptor/Toll-like receptor (IL-1R1/TLR4) innate immunity signal plays a pivotal role in neuronal hyperexcitability underlying seizures in rodents. Since this pathway is activated in neurons and glia in human epileptogenic foci, it represents a potential target for developing drugs interfering with the mechanisms of epileptogenesis that lead to spontaneous seizures. The lack of such drugs represents a major unmet clinical need. We tested therefore novel therapies inhibiting the IL-1R1/TLR4 signaling in an established murine model of acquired epilepsy. We used an epigenetic approach by injecting a synthetic mimic of micro(mi)RNA-146a that impairs IL1R1/TLR4 signal transduction, or we blocked receptor activation with antiinflammatory drugs. Both interventions when transiently applied to mice after epilepsy onset, prevented disease progression and dramatically reduced chronic seizure recurrence, while the anticonvulsant drug carbamazepine was ineffective. We conclude that IL-1R1/TLR4 is a novel potential therapeutic target for attaining disease-modifications in patients with diagnosed epilepsy.

Keywords: Disease-modification; Epilepsy; Hyperexcitability; Neuroinflammation; Seizures.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / administration & dosage*
  • Anticonvulsants / administration & dosage*
  • Carbamazepine / pharmacology
  • Cyanobacteria
  • Dipeptides / administration & dosage
  • Disease Models, Animal
  • Epilepsy / drug therapy
  • Epilepsy / physiopathology
  • Epilepsy / therapy*
  • Hippocampus / physiopathology
  • Kainic Acid
  • Lipopolysaccharides / administration & dosage
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / administration & dosage*
  • Oligonucleotides / administration & dosage
  • Random Allocation
  • Receptors, Interleukin-1 Type I / antagonists & inhibitors*
  • Receptors, Interleukin-1 Type I / metabolism
  • Time Factors
  • Toll-Like Receptor 4 / antagonists & inhibitors*
  • Toll-Like Receptor 4 / metabolism
  • para-Aminobenzoates / administration & dosage

Substances

  • 1-(2-((1-(4-amino-3-chlorophenyl)methanoyl)amino)-3,3-dimethylbutanoyl)pyrrolidine-2-carboxylic acid
  • Anti-Inflammatory Agents, Non-Steroidal
  • Anticonvulsants
  • Dipeptides
  • IL1R1 protein, mouse
  • Lipopolysaccharides
  • MicroRNAs
  • Mirn146 microRNA, mouse
  • Oligonucleotides
  • Receptors, Interleukin-1 Type I
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • para-Aminobenzoates
  • Carbamazepine
  • Kainic Acid