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Journal of Neuroscience, Vol 7, 3343-3349, Copyright © 1987 by Society for Neuroscience
Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil
R Gill, AC Foster and GN Woodruff
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
The neuroprotective effects of MK-801, a noncompetitive antagonist of N-
methyl-D-aspartate (NMDA) receptors, were evaluated in models of cerebral
ischemia using Mongolian gerbils. Bilateral occlusion of the carotid
arteries for a period of 5 min resulted in a consistent pattern of
degeneration of hippocampal CA1 and CA2 pyramidal neurons, which was
quantified using an image analyzer. Systemic administration of MK-801
(0.01-10 mg/kg, i.p.) 1 hr prior to the occlusion caused a dose- dependent
protection of the CA1 and CA2 neurons. The ED50 value for neuroprotection
by MK-801 was calculated to be 0.3 mg/kg, and at doses greater than or
equal to 3 mg/kg the majority of animals were completely protected against
the ischemic insult. Systemic administration of MK-801 (1 or 10 mg/kg,
i.p.) 1 hr prior to unilateral occlusion of the right carotid artery
resulted in significant protection against hippocampal neurodegeneration
following 10 min of occlusion, and increased the survival rate after 30 min
of occlusion. The potent neuroprotective effects of MK-801 in these
cerebral ischemia models add further weight to the evidence that NMDA
receptors are involved in the mechanism of ischemia-induced neuronal
degeneration.
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