Correlates of delayed neuronal damage and neuroprotection in a rat model of cardiac-arrest-induced cerebral ischemia

Numerous studies over the past three decades have used rodent models of cer ebral ischemia. To measure the postischemic outcome, the majority of these studies used histopathology as the method of choice both quantitatively and qualitatively. No functional measure of postischemic outcome has been prov ed to correlate well with the histopathological one. The rat chest compress ion model of cardiac-arrest-induced global cerebral ischemia was used in th e present study. Two separate measures of neuronal damage at 7 days postisc hemia were performed: (a) histologically, by counting normal pyramidal cell bodies in the mid-CA1 hippocampal region of the rat brain, in hematoxylin- eosin-stained, paraffin-embedded 6-mu m sections, and (b) electrophysiologi cally, by counting the number of 400 mu m hippocampal slices in which it wa s possible to evoke a normal (greater than or equal to 10 mV) CA1 populatio n spike by orthodromic stimulation of the Schaffer collaterals. The correla tion between these two measures was tested in the following groups of rats: (a) control, untreated group, (b) MK-801-treated groups (0.03 to 1.0 mg/kg given i.p. shortly after ischemia), (c) diltiazem-treated (DILT) groups 1. 0 to 30 mg/kg, given i.p. shortly after ischemia, and (d) a group treated w ith a combination of the mio drugs together(0.1 mg/kg MK-801 + 3.0 mg/kg DI LT given i.p. shortly after ischemia). The two measures of postischemic out come were highly correlated in all groups studied. Both MK-801 and DILT exh ibited a dose-dependent neuroprotective effect. When administered together, a synergy between the neuroprotective effect of MK-801 and DILT was observ ed. At the doses used, minimal or no side effects of either MK-801 or DILT were observed. (C) 1999 Elsevier Science B.V. All rights reserved.