Lamotrigine protects hippocampal CA1 neurons from ischemic damage after cardiac arrest.
OBJECTIVE
Lamotrigine (LTG) is an anticonvulsant drug whose mechanism of action may involve the inhibition of glutamate release by blocking voltage-dependent sodium channels. Glutamate neurotoxicity may contribute to cerebral ischemic damage after recovery from cardiac arrest. Thus, LTG may prevent the brain damage associated with global cerebral ischemia by reducing the release of glutamate from presynaptic vesicles during the ischemic insult or the early recovery period.


METHODS
LTG was studied in cardiac arrest-induced global cerebral ischemia with reperfusion in rats. In the first set of experiments, LTG (100 mg/kg, p.o.) was administered before induction of ischemia; and in the second experiment, LTG (10 mg/kg, i.v.) was given 15 minutes after ischemia and a second dose (10 mg/kg,i.v.) was given 5 hours later.


RESULTS
In both experiments LTG reduced the damage to the hippocampal CA1 cell population by greater than 50%. Neuroprotection was not associated with changes in brain temperature or plasma glucose concentration. Plasma concentrations of LTG ranged between 8 and 13 micrograms/mL. Patients taking LTG as a monotherapy for epilepsy typically have plasma levels of LTG in the 10 to 15 micrograms/mL range.


CONCLUSIONS
These data suggest that LTG may be effective in preventing brain damage after recovery from cardiac arrest. Patients on LTG monotherapy for epilepsy have plasma concentrations very similar to those found to be neuroprotective in this study. Although difficult to extrapolate, our data suggest that LTG at neuroprotective doses may be well tolerated by humans.
Crumrine
R C
RC
Department of Molecular Pharmacology, Glaxo Wellcome Inc., Research Tringle Park, NC 27709-3398, USA. rcc41549@glaxo.com
Bergstrand
K
K
Cooper
A T
AT
Faison
W L
WL
Cooper
B R
BR
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000209:etiology* / Q000473:pathology*; D006323:Heart Arrest / Q000150:complications*; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology*; D000077213:Lamotrigine; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009994:Osmolar Concentration; D051381:Rats; D011916:Rats, Inbred F344; D014227:Triazines / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*
D000927:Anticonvulsants; D018696:Neuroprotective Agents; D014227:Triazines; D000077213:Lamotrigine