Downregulation of CD40L-CD40 attenuates seizure susceptibility and severity of seizures

Sci Rep. 2021 Aug 26;11(1):17262. doi: 10.1038/s41598-021-96760-3.

Abstract

Unregulated neuro-inflammation mediates seizures in temporal lobe epilepsy (TLE). Our aim was to determine the effect of CD40-CD40L activation in experimental seizures. CD40 deficient mice (CD40KO) and control mice (wild type, WT) received pentenyltetrazole (PTZ) or pilocarpine to evaluate seizures and status epilepticus (SE) respectively. In mice, anti-CD40L antibody was administered intranasally before PTZ. Brain samples from human TLE and post-seizure mice were processed to determine CD40-CD40L expression using histological and molecular techniques. CD40 expression was higher in hippocampus from human TLE and in cortical neurons and hippocampal neural terminals after experimental seizures. CD40-CD40L levels increased after seizures in the hippocampus and in the cortex. After SE, CD40L/CD40 levels increased in cortex and showed an upward trend in the hippocampus. CD40KO mice demonstrated reduction in seizure severity and in latency compared to WT mice. Anti-CD40L antibody limited seizure susceptibility and seizure severity. CD40L-CD40 interaction can serve as a target for an immuno-therapy for TLE.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD40 Antigens / genetics
  • CD40 Antigens / metabolism*
  • CD40 Ligand / metabolism*
  • Disease Models, Animal*
  • Down-Regulation*
  • Epilepsy, Temporal Lobe / chemically induced
  • Epilepsy, Temporal Lobe / genetics
  • Epilepsy, Temporal Lobe / metabolism*
  • Genetic Predisposition to Disease / genetics
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Male
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neurons / metabolism
  • Pentylenetetrazole
  • Seizures / chemically induced
  • Seizures / genetics
  • Seizures / metabolism*
  • Severity of Illness Index
  • Status Epilepticus / metabolism

Substances

  • CD40 Antigens
  • CD40 Ligand
  • Pentylenetetrazole