Neuroprotective properties of the novel antiepileptic drug levetiracetam in the rat middle cerebral artery occlusion model of focal cerebral ischemia.
Levetiracetam (LEV) is a new antiepileptic drug with a promising preclinical profile involving both anticonvulsant and antiepileptogenic effects in kindling models. The latter stimulated the present study to compare its neuroprotective properties with the potent and selective, non-competitive NMDA antagonist, MK-801, in the rat middle cerebral artery occlusion model. Twenty-four hours after a transient occlusion of 90 minutes the animals were sacrificed and infarct volume and lesion distribution were determined from stained coronal sections. LEV was administered by intraperitoneal (i.p.) bolus injections of 5.5, 11, 22 and 44 mg x kg(-1), 30 minutes before occlusion followed by a continuous 24 hour i.p. infusion of 1.25, 2.6, 5.1 and 10.2 mg x kg(-1) per hour, respectively. LEV administration did not alter body temperature but reduced the infarct volume by 33% (P< 0.05) at the highest dose tested. An i.p. bolus injection of 0.04, 0.12 and 0.4 mg x kg(-1) of MK-801 followed by continuous i.p. infusion of 0.036, 0.108 and 0.36 mg x kg(-1) per hour, reduced the infarct volume by 49, 51 and 74% (P< 0.05), respectively. However, only the highest dose of MK-801 induced a significant reduction in the infarct volume (P< 0.05) and this was associated with hypothermia. These results suggest that LEV possesses neuroprotective properties which may be relevant for its antiepileptogenic action.
Hanon
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UCB S.A. Pharma Sector, Preclinical CNS Research, Chemin du Foriest, B-1420 Braine-1' Alleud, Belgium. etienne.hanon@ucb-group.com
Klitgaard
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D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D001157:Arterial Occlusive Diseases / Q000188:drug therapy; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000098:blood supply* / Q000187:drug effects*; D002545:Brain Ischemia / Q000188:drug therapy*; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D000077287:Levetiracetam; D008297:Male; D020768:Middle Cerebral Artery / Q000187:drug effects*; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D010889:Piracetam / Q000031:analogs & derivatives / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D000077287:Levetiracetam; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D010889:Piracetam