Transient Increase of interleukin-1β After Prolonged Febrile Seizures Promotes Adult Epileptogenesis Through Long-Lasting Upregulating Endocannabinoid Signaling

Sci Rep. 2016 Feb 23;6:21931. doi: 10.1038/srep21931.

Abstract

It remains unclear how infantile febrile seizures (FS) enhance adult seizure susceptibility. Here we showed that the transient increase of interleukin-1β (IL-1β) after prolonged FS promoted adult seizure susceptibility, which was blocked by interleukin-1 receptor antagonist (IL-1Ra) within a critical time window. Postnatal administered IL-1β alone mimicked the effect of FS on adult seizure susceptibility. IL-1R1 knockout mice were not susceptible to adult seizure after prolonged FS or IL-1β treatment. Prolonged FS or early-life IL-1β treatment increased the expression of cannabinoid type 1 receptor (CB1R) for over 50 days, which was blocked by IL-1Ra or was absent in IL-1R1 knockout mice. CB1R antagonist, knockdown and endocannabinoid synthesis inhibitor abolished FS or IL-1β-enhanced seizure susceptibility. Thus, this work identifies a pathogenic role of postnatal IL-1β/IL-1R1 pathway and subsequent prolonged prominent increase of endocannabinoid signaling in adult seizure susceptibility following prolonged FS, and highlights IL-1R1 as a potential therapeutic target for preventing the development of epilepsy after infantile FS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / genetics*
  • Animals
  • Benzoxazines / pharmacology
  • Cannabinoid Receptor Antagonists / pharmacology
  • Cyclohexanones / pharmacology
  • Gene Expression Regulation
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Interleukin 1 Receptor Antagonist Protein / antagonists & inhibitors
  • Interleukin 1 Receptor Antagonist Protein / genetics*
  • Interleukin 1 Receptor Antagonist Protein / metabolism
  • Interleukin-1beta / antagonists & inhibitors
  • Interleukin-1beta / genetics*
  • Interleukin-1beta / metabolism
  • Lipoprotein Lipase / antagonists & inhibitors
  • Lipoprotein Lipase / genetics
  • Lipoprotein Lipase / metabolism
  • Mice
  • Mice, Knockout
  • Morpholines / pharmacology
  • Naphthalenes / pharmacology
  • Piperidines / pharmacology
  • Pyrazoles / pharmacology
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • Rats, Sprague-Dawley
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors
  • Receptor, Cannabinoid, CB1 / genetics*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Rimonabant
  • Seizures / genetics*
  • Seizures / metabolism
  • Seizures / pathology
  • Seizures / physiopathology
  • Seizures, Febrile / genetics*
  • Seizures, Febrile / metabolism
  • Seizures, Febrile / pathology
  • Seizures, Febrile / physiopathology
  • Signal Transduction
  • Tissue Culture Techniques

Substances

  • Benzoxazines
  • Cannabinoid Receptor Antagonists
  • Cyclohexanones
  • IL1B protein, mouse
  • Il1rn protein, mouse
  • Interleukin 1 Receptor Antagonist Protein
  • Interleukin-1beta
  • Morpholines
  • Naphthalenes
  • Piperidines
  • Pyrazoles
  • RNA, Small Interfering
  • Receptor, Cannabinoid, CB1
  • Win 55212-2
  • 1,6-bis(cyclohexyloximinocarbonyl)hexane
  • Lipoprotein Lipase
  • Rimonabant