BW619C89, a glutamate release inhibitor, protects against focal cerebral ischemic damage.
OBJECTIVE
The excitatory amino acid neurotransmitter glutamate is involved in excitotoxic brain injury and neurodegeneration after cerebral ischemia. Therefore, compounds that block the release of glutamate may be useful as cerebroprotective agents. The purpose of this study was to evaluate the cerebroprotective properties of a glutamate release inhibitor, BW619C89.


METHODS
In the studies reported here, the effect of BW619C89 [4-amino-2-(4-methyl-1-piperazinyl)-5-(2,3,5-trichlorophenyl)pyrimidine] on neurotransmitter release (endogenous amino acids, gamma-aminobutyric acid, and acetylcholine) from slices of rat brain cerebral cortex in vitro has been determined. The neuroprotective efficacy of BW619C89 has been evaluated using the middle cerebral artery occlusion model of focal cerebral ischemia in the Fischer 344 rat.


RESULTS
In the in vitro studies, BW619C89 inhibited veratrine- (but not potassium-) evoked release of both endogenous glutamate and aspartate from rat cerebral cortex slices with IC50 values of approximately 5 microM. BW619C89 was approximately 10-fold less potent to inhibit veratrine-evoked 3H-gamma-aminobutyric acid release (IC50 = 51 microM), fourfold less potent to inhibit 3H-acetylcholine release (IC50 = 21 microM), and at 10 microM had only weak activity at excitatory amino acid (N-methyl-D-aspartate, kainate, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding sites. When administered intravenously to Fischer 344 rats 5 minutes after permanent middle cerebral artery occlusion, BW619C89 produced marked reductions of both total (cortex and basal ganglia) and cortical infarct volumes. Cortical infarct size was reduced by 20% at a dose of BW619C89 of 5 mg/kg (n = 6, not significant); 43% at 10 mg/kg (n = 8, P < .01); 59% at 20 mg/kg (n = 8, P < .001); 61% at 30 mg/kg (n = 8, P < .001), and 53% at 40 mg/kg (n = 8, P < .001). BW619C89 at doses of 20 and 30 mg/kg also significantly reduced noncortical (basal ganglia) infarct volumes, demonstrating that a proportion of this tissue also appears to be salvageable. Behavioral effects observed were dose related, generally minor, and at doses of 20 mg/kg IV and above consisted of body tremor and mild ataxia lasting approximately 2 hours.


CONCLUSIONS
These results suggest that glutamate release inhibitors such as BW619C89 may provide an alternative to excitatory amino acid receptor antagonists in the treatment of focal cerebral ischemia and stroke.
Leach
M J
MJ
Department of Pharmacology, Wellcome Research Laboratories, Beckenham, Kent, England, UK.
Swan
J H
JH
Eisenthal
D
D
Dopson
M
M
Nobbs
M
M
D000109:Acetylcholine / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001930:Brain Injuries / Q000517:prevention & control*; D002545:Brain Ischemia / Q000517:prevention & control*; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D014702:Veratrine / Q000037:antagonists & inhibitors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000596:Amino Acids; D018377:Neurotransmitter Agents; D010879:Piperazines; D011743:Pyrimidines; D005680:gamma-Aminobutyric Acid; D014702:Veratrine; D000109:Acetylcholine; C081980:sipatrigine