Antagonism of peripheral inflammation reduces the severity of status epilepticus.
Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium-pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1beta levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1beta is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.
Marchi
Nicola
N
Cerebrovascular Research, Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44106, USA.
Fan
Qingyuan
Q
Ghosh
Chaitali
C
Fazio
Vincent
V
Bertolini
Francesca
F
Betto
Giulia
G
Batra
Ayush
A
Carlton
Erin
E
Najm
Imad
I
Granata
Tiziana
T
Janigro
Damir
D
D000200:Action Potentials; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000097:blood; D007962:Leukocytes / Q000187:drug effects; D018021:Lithium Chloride / Q000008:administration & dosage; D008297:Male; D008839:Microelectrodes; D010862:Pilocarpine / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy*; D013826:Theta Rhythm
D000894:Anti-Inflammatory Agents, Non-Steroidal; D053590:Interleukin 1 Receptor Antagonist Protein; D053583:Interleukin-1beta; D010862:Pilocarpine; D018021:Lithium Chloride