Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in the gerbil

Abstract

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.

Neuroprotective Effect of YM9OK, an AMPA-Receptor Antagonist,against Delayed Neuronal Death Induced by Transient Global Cerebral Ischemia in Gerbils and Rats.

“…Gluta mate antagonists are therefore considered a candidate therapy for the treatment of acute stroke. Numerous studies on the neuroprotective effect of N-methyl-D aspartate (NMDA)-type glutamate-receptor antagonists have been reported (2)(3)(4)(5)(6)(7). However, the use of NMDA receptor antagonists is limited because of side effects they produce including psychotomimetic action (8), learn ing impairment (9) and vacuolization of cerebrocortical neurons (10, 11).…”

Neuroprotective activity of chlormethiazole following transient forebrain ischaemia in the gerbil

“…The extent of neurodegeneration in the hippocampal CA1/CA2 region was routinely determined by a method similar to that described by Gill et al (1987). One section from each brain was photographed and measurements taken from both hippocampi.…”

Staurosporine, a Novel Protein Kinase C Inhibitor, Prevents Postischemic Neuronal Damage in the Gerbil and Rat

“…Staurosporine (Tamaoki et al, 1986), KT5720 (Kase et al, 1987), and KT5822 (Kase et al, 1987) were used as inhibitors of PKC, cyclic AMP-dependent protein kinase, and cyclic GMP dependent protein kinase, respectively. Mongolian gerbils have been commonly used to estimate the protective effects of drugs against ischemic CAl py ramidal cell damage (Kirino, 1982;Kirino et al, 1986a,b;Gill et al, 1987;Izumiyama and Kogure, 1988), although involvement of the hippocampus in the seizure activities characteristic of this animal has been reported (Paul et al, 198 1;Peterson et al, 1985). Interestingly, the protective effect of drugs against ischemic CAl damage is more pronounced in gerbil models than rat models.…”