Neuroprotective properties of the novel antiepileptic lamotrigine in a gerbil model of global cerebral ischemia.
OBJECTIVE
Elevated glutamate levels are thought to be a primary cause of neuronal death after global cerebral ischemia. The purpose of this study was to investigate the potential neuroprotective effects of lamotrigine, a novel antiepileptic drug that inhibits the release of glutamate in vitro, with both behavioral and histological measures of global ischemia in gerbils.


METHODS
The common carotid arteries of gerbils were occluded for either 5, 10, or 15 minutes. Twenty-one days after reperfusion, gerbils were tested for impairments in a spatial memory task (Morris water maze). After water maze testing the animals were killed, and damage to hippocampal pyramidal cells was assessed. The effect of lamotrigine on the behavioral and histological outcome of either 5 or 15 minutes of global ischemia was evaluated.


RESULTS
Bilateral occlusion of the common carotid arteries for 5 minutes resulted in severe degeneration of hippocampal CA1 and CA2 pyramidal cells. Lamotrigine significantly prevented loss of hippocampal CA1 neurons when administered acutely (100 mg/kg PO) immediately after reperfusion or when administered in two equal doses of 30 or 50 mg/kg 2 hours before and immediately after reperfusion. Gerbils subjected to 5 minutes of ischemic insult were not impaired in their ability to solve a spatial memory task 21 days after cerebral ischemia. However, gerbils subjected to 10 and 15 minutes of carotid artery occlusion showed significant impairment in their ability to solve a water maze task. Lamotrigine significantly protected against the cognitive deficits associated with 15 minutes of cerebral ischemia. Histologically, increased durations of cerebral ischemia resulted in a progressive loss of CA1, CA2, and CA3 pyramidal cells. Lamotrigine completely protected gerbils exposed to 15 minutes of cerebral ischemia against CA3 cell loss and greatly reduced damage to the CA1 and CA2 cell tracts of the hippocampus. Lamotrigine also reduced the mortality associated with 15 minutes of ischemia.


CONCLUSIONS
Lamotrigine had neuroprotective effects in a gerbil model of global cerebral ischemia. Lamotrigine protected gerbils against behavioral deficits resulting from 15 minutes of carotid occlusion and also prevented histological damage resulting from 5 and 15 minutes of global cerebral ischemia.
Wiard
R P
RP
Division of Pharmacology, Burroughs Wellcome Co, Research Triangle Park, NC 27709.
Dickerson
M C
MC
Beek
O
O
Norton
R
R
Cooper
B R
BR
D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use; D001157:Arterial Occlusive Diseases / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001923:Brain Chemistry; D002545:Brain Ischemia / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002340:Carotid Artery Diseases / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D005849:Gerbillinae; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D000077213:Lamotrigine; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*; D017966:Pyramidal Cells / Q000187:drug effects / Q000473:pathology; D015427:Reperfusion Injury / Q000473:pathology / Q000517:prevention & control; D014227:Triazines / Q000008:administration & dosage / Q000097:blood / Q000627:therapeutic use*
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D014227:Triazines; D018698:Glutamic Acid; D000077213:Lamotrigine