Combination therapy with nimodipine and dizocilpine in a rat model of transient forebrain ischemia.

Abstract

Background and Purpose:We explored the effectiveness of dual blockade of calcium channels in preventing ischemic necrosis in a rat model of transient forebrain ischemia.Methods: To assess all the major brain regions, the entire brain was subseriallv sectioned and examined histologically 1 week after ischemia in 44 male Wistar rats. Brain temperature was monitored and controlled to avoid hypothermia or intergroup temperature differences at the time drugs were administered. All regimens were begun 20 minutes after the ischemia. Treated animals received either the L-type calcium channel blocker nimodipine (0.25 /ig/minx24-hour i.v. infusion), the noncompetitive A'-raethyl-D-aspartate receptor antagonist MK-801 (dizocilpine; 5 mg/kg i.v.), or both regimens in combination.Results: In the neocortex (p<0.05) and striatum (p<0.05), only double-treated animals showed a statistically significant reduction in neuronal necrosis. Dual therapy eliminated neuronal necrosis in the caudate nucleus entirely. In the septa I (densely ischemic) hippocampus, protection was weak and inconsistent (0.012<p<0.788), but in the temporal (incompletely ischemic) hippocampus, the dualtreated group showed the most significant reduction (p<0.006).Conclusions :

In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

“…The additional protective effect of MK-801 and nimodipine has also been reported in models of ischaemia and in tissue trauma in culture (Greenberg et al, 1990;Rod & Auer, 1992;Uematsu et al, 1991;Regan & Choi, 1994). Furthermore, the degree of protection showed a timedependent effect with regard to the start of the drug treatment after the NMDA-injection.…”

Effect of Delayed MK-801 (Dizocilpine) Treatment with or without Immediate Postischemic Hypothermia on Chronic Neuronal Survival after Global Forebrain Ischemia in Rats

“…To determine critically whether acti vated microglia or invading macrophages are re sponsible for delayed cell death after postischemic hypothermia, additional experiments are required in which macrophage accumulation is pharmacolog ically reduced (Giulian and Robertson, 1990;Chopp et ai., 1994). Although early studies of global isch emia reported neuroprotection with early postisch emic MK-801 treatment (Gill et ai., 1988;Rod and Auer, 1992), more recent studies have failed to demonstrate histopathological protection (Nellgard et ai., 1991;Nellgard and Wieloch, 1992). The fact that, in this study, delayed MK-801 treatment alone failed to provide protection of the CAl hippocam pus indicates that one beneficial effect of postisch emic hypothermia is to delay the onset of irrevers ible neuronal injury, thereby extending the thera peutic window for secondary pharmacotherapy.…”

“…Ikonomi dou and colleagues (1989) have shown that hypo thermia enhances the protective effect of MK-801 against hypoxic-ischemic brain damage in infant rats. In the setting of transient forebrain ischemia, the combination of nimodipine and MK-801 begun 20 min after ischemia was reported to lead to pro tection of the neocortex, striatum, and temporal hippocampus (Rod and Auer, 1992 colleagues (1990) have also reported that combined therapy with hypothermia plus dextromethorphan protected the neocortex from injury in excess of the protection conferred by either hypothermia or dex tromethorphan alone. Unlike previous studies, hy pothermia and MK-801 treatments were given at different postischemic periods in the present study.…”

“…Although the dorsolateral stria tum is considered a selectively vulnerable brain region after prolonged periods of transient fore brain ischemia (Pulsinelli et aI., 1982), relatively brief periods of global ischemia have been reported to result in 6nly mild and inconsistent damage to the striatum (Lin et aI., 1990;Rod and Auer, 1992). In previous studies, however, relatively short survival periods were investigated.…”

Mechanism of Action and Persistence of Neuroprotection by Cell-Permeant Ca2+ Chelators

“…However, the rats were observed intermittently through out this time to ensure that no gross behavioral or phys iological abnormalities occurred (e.g., seizures or respi ratory compromise). Since high doses of MK-801 produce obtundation (Rod and Auer, 1992), we used a dose of 0.5 mg/kg, as this was shown to protect against focal isch emic damage in the rat (Park et aI., 1988a) while still allowing the animal to awaken following termination of the anesthetic.…”