title: Seizure-induced brain-borne inflammation sustains seizure recurrence and blood-brain barrier damage.
abstract: OBJECTIVE
  Epilepsy is a common neurological disorder characterized by recurrent seizures often unresponsive to pharmacological treatment. Brain inflammation is considered a crucial etiopathogenetic mechanism of epilepsy that could be targeted to control seizures. Specific inflammatory mediators overexpressed in human epileptogenic foci are known to promote seizures in animal models. We investigated whether seizures induce brain inflammation independently on extracerebral factors. We also investigated whether brain-borne inflammation is required and sufficient to maintain seizure activity and whether it causes blood-brain barrier (BBB) impairment. We addressed these questions by studying the relation between seizures, inflammation, and BBB permeability in a brain preparation isolated from extracerebral compartments.
  
  
  METHODS
  Epileptiform activity was induced by arterial perfusion of bicuculline in the in vitro isolated guinea pig brain. Seizure-induced brain inflammation was evaluated by quantitative immunohistochemical analysis of interleukin (IL)-1β in parenchymal cells. BBB damage was assessed by extravasation of intravascular fluorescein isothiocyanate-albumin. The effects of arterially perfused anakinra, a human recombinant IL-1β receptor antagonist, were investigated on epileptiform discharges, brain inflammation, and BBB damage.
  
  
  RESULTS
  Seizure induction in the absence of extracerebral factors promoted the release of IL-1β from brain resident cells and enhanced its biosynthesis in astrocytes. Anakinra rapidly terminated seizures, prevented their recurrence, and resolved seizure-associated BBB breakdown.
  
  
  CONCLUSIONS
  Seizures initiate brain inflammation in glia and promote BBB damage that is independent of either leukocytes or blood-borne inflammatory molecules. Brain inflammation contributes to the duration and recurrence of seizures. This study supports the use of specific anti-inflammatory drugs in clinical conditions that present with intractable recurrent seizures.
authors: Unit of Experimental Neurophysiology and Epileptology, Foundation Carlo Besta Neurological Institute, Milan, Italy.
authors: Laura
authors: L
authors: Librizzi
authors: Francesco
authors: F
authors: Noè
authors: Annamaria
authors: A
authors: Vezzani
authors: Marco
authors: M
authors: de Curtis
authors: Teresa
authors: T
authors: Ravizza
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001640:Bicuculline; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004660:Encephalitis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D058787:GABA-A Receptor Antagonists; D006168:Guinea Pigs; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology / Q000627:therapeutic use; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors / Q000378:metabolism; D012008:Recurrence; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*
chemical_list: D058787:GABA-A Receptor Antagonists; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D001640:Bicuculline