Cerebroprotective effect of lamotrigine after focal ischemia in rats.
OBJECTIVE
Glutamate receptor antagonists are protective in animal models of focal cerebral ischemia. Lamotrigine (3,5-diamino-6-[2,3-dichlorophenyl]-1,2,4-triazine) is an anticonvulsant drug that blocks voltage-gated sodium channels and inhibits the ischemia-induced release of glutamate. We describe the cerebroprotective effect of lamotrigine (as the isethionate salt) after middle cerebral artery occlusion in rats.


METHODS
Neurological deficit and infarct volume (visualized by the lack of reduction of 2,3,5-triphenyltetrazolium chloride) 24 hours after permanent left middle cerebral artery occlusion were studied in Fischer rats (n = 8 per group per dose).


RESULTS
Lamotrigine at 20 mg/kg i.v. over 10 minutes administered immediately after middle cerebral artery occlusion reduced total infarct volume by 31% and cortical infarct volume by 52%. Lamotrigine at 8 mg/kg i.v. over 10 minutes reduced cortical infarct volume by 38%. Lamotrigine at 50 mg/kg i.v. for 10 minutes was not cerebroprotective and induced a decrease of 29 +/- 15 mm Hg in mean arterial blood pressure (P < .05, n = 8). The optimum dose of lamotrigine (20 mg/kg i.v. over 10 minutes) when administered with a 1-hour delay after middle cerebral artery occlusion reduced cortical infarct volume by 41%. Lamotrigine (20 mg/kg i.v. over 10 minutes) with a 2-hour delay after middle cerebral artery occlusion was ineffective. Neurological deficits after 24 hours were improved after immediate treatment with lamotrigine at 20 mg/kg i.v. over 10 minutes.


CONCLUSIONS
The cerebroprotective effect of lamotrigine in rats is limited to a narrow dose range between 8 and 20 mg/kg. Lamotrigine or analogous compounds may be useful when given shortly after the onset of stroke.
Smith
S E
SE
Department of Neurology, Institute of Psychiatry, De Crespigny Park, Denmark Hill, UK.
Meldrum
B S
BS
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000473:pathology; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000077213:Lamotrigine; D008297:Male; D010879:Piperazines / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D051381:Rats; D011916:Rats, Inbred F344; D015222:Sodium Channels / Q000187:drug effects; D014227:Triazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*
D018691:Excitatory Amino Acid Antagonists; D010879:Piperazines; D011743:Pyrimidines; D015222:Sodium Channels; D014227:Triazines; C078265:5-(2,3,5-trichlorophenyl)pyrimidine-2,4-diamine ethane sulfonate; C081980:sipatrigine; D000077213:Lamotrigine