Peripheral administration of Interleukin-1 Receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat.
We assessed the efficacy of recombinant human interleukin-1 receptor antagonist (rhIL-1ra) on brain injury and edema formation after permanent middle cerebral artery occlusion (MCAo) in the rat. Previous studies showed that low amounts of rhIL-1ra injected directly into the brain significantly decreased infarct size after MCAo or excitotoxic injury in rats. Peripheral administration of rhIL-1ra (100 mg/kg sc at 0, 4, 8, 12, and 18 h after MCAo) significantly inhibited infarct size, by 46% (P < 0.05), measured at 24h. This was greater than the effect of MK801 administered immediately after MCAo (4 mg/kg ip, 0 h) which did not significantly reduce infarct size. rhIL-1ra (100 mg/kg also significantly inhibited cerebral edema formation by 49% (p< 0.05 measured 24 h after MCAo, but did not reduce edema formation measured 2 h after MCAo, but did not reduce edema formation measured 2 h after MCAo. Inhibition of infarction by rhIL-1ra was dependent on dose and time of administration. Together the results demonstrate that peripherally administered rhIL-1ra at high doses is able to mimic the efficacy of low dose of rhIL-1ra administered directly into the brain in a rodent model of stroke and that protection observed with rhIL-1ra was better than that offered by MK801 in this model.
Relton
J K
JK
Department of Preclinical Pharmacology, Amgen Inc, Boulder, Colorado 80301, USA.
Martin
D
D
Thompson
R C
RC
Russell
D A
DA
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001925:Brain Damage, Chronic / Q000517:prevention & control*; D001929:Brain Edema / Q000517:prevention & control; D002545:Brain Ischemia / Q000150:complications*; D002544:Cerebral Infarction / Q000473:pathology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins
D001786:Blood Glucose; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D016291:Dizocilpine Maleate