Recent studies have strongly implicated the excitatory
neurotransmitter glutamate in the cascade of pathological mechanisms that cause neuronal loss after certain types of
brain ischemia. The neurotoxic effects of
glutamate are mediated, at least in global
ischemia, via
NMDA receptors. In the present study we have examined the effects of compounds that possess
NMDA receptor antagonist properties (
ifenprodil,
SL 82.0715 [(+/-)-alpha-(4-chlorophenyl)-4-[(4-fluorophenyl)methyl]- 1-piperidineethanol] and 1-[1-(2-thienyl)cyclohexyl]
piperidine) on the histological consequences of focal, as opposed to global,
cerebral ischemia in both the rat and the cat.
Ifenprodil (0.3-3 mg/kg i.v.) administered as a perfusion over 3 hr after occlusion of the feline middle cerebral artery reduced the volume of infarcted tissue (measured 4 days after occlusion) in a dose-related manner. At the highest dose a 42% reduction of infarcted volume was noted, essentially in cortical tissue. In an identical protocol, a derivative of
ifenprodil,
SL 82.0715, reduced the volume of
infarction in a manner comparable to that described for
ifenprodil. As
SL 82.0715 possesses better p.o. bioavailability, this compound was also evaluated in the rat, again after
middle cerebral artery occlusion. First administered 30 min after the induction of
ischemia,
SL 82.0715 (1 and 10 mg/kg p.o.) reduced
infarction volume by 34 and 48%, respectively. The quantitative histology was performed 2 days after
middle cerebral artery occlusion. The noncompetitive receptor antagonist, 1-[1-(2-thienyl)cyclohexyl]
piperidine, administered (1 mg/kg i.p.) before the induction of focal
ischemia, similarly and significantly decreased the final volume of
infarction. As both
ifenprodil and
SL 82.0715 are noncompetitive antagonists of the
NMDA receptor, two conclusions may be drawn from the present investigation. First,
NMDA antagonism by
ifenprodil and its derivative is an effective approach for tissue sparing in animal models of
stroke and
brain infarction. Second, these pharmacological observations provide evidence for the involvement of
excitatory amino-acid induced-neurotoxicity in the evolution and consequences of focal
cerebral ischemia.