LAMOTRIGINE PROTECTS HIPPOCAMPAL CA1 NEURONS FROM ISCHEMIC DAMAGE AFTER CARDIAC-ARREST

Background and Purpose Lamotrigine (LTG) is an anticonvulsant drug who se mechanism of action may involve the inhibition of glutamate release by blocking voltage-dependent sodium channels. Glutamate neurotoxicit y may contribute to cerebral ischemic damage after recovery from cardi ac arrest. Thus, LTG may prevent the brain damage associated with glob al cerebral ischemia by reducing the release of glutamate from presyna ptic vesicles during the ischemic insult or the early recovery period. Methods LTG was studied in cardiac arrest-induced global cerebral isc hemia with reperfusion in rats. In the first set of experiments, LTG ( 100 mg/kg, PO) was administered before induction of ischemia; and in t he second experiment, LTG (10 mg/kg, IV) was given 15 minutes after is chemia and a second dose (10 mg/kg,IV) was given 5 hours later. Result s In both experiments LTG reduced the damage to the hippocampal CA1 ce ll population by greater than 50%. Neuroprotection was not associated with changes in brain temperature or plasma glucose concentration. Pla sma concentrations of LTG ranged between 8 and 13 mu g/mL. Patients ta king LTG as a monotherapy for epilepsy typically have plasma levels of LTG in the 10 to 15 mu g/mL range. Conclusions These data suggest tha t LTG may be effective in preventing brain damage after recovery from cardiac arrest. Patients on LTG monotherapy for epilepsy have plasma c oncentrations very similar to those found to be neuroprotective in thi s study. Although difficult to extrapolate, our data suggest that LTG at neuroprotective doses may be well tolerated by humans.