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 cerebral 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 proved to correlate well with the histopathological one. The rat chest compression model of cardiac-arrest-induced global cerebral ischemia was used in the present study. Two separate measures of neuronal damage at 7 days postischemia 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-microm sections, and (b) electrophysiologically, by counting the number of 400 microm hippocampal slices in which it was possible to evoke a normal (>/=10 mV) CA1 population spike by orthodromic stimulation of the Schaffer collaterals. The correlation 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 with a combination of the two drugs together (0.1 mg/kg MK-801+3.0 mg/kg DILT given i.p. shortly after ischemia). The two measures of postischemic outcome were highly correlated in all groups studied. Both MK-801 and DILT exhibited a dose-dependent neuroprotective effect. When administered together, a synergy between the neuroprotective effect of MK-801 and DILT was observed. At the doses used, minimal or no side effects of either MK-801 or DILT were observed.
Li
M M
MM
Brain Attack Research Laboratory, Department of Anesthesiology, School of Medicine, University of Louisville, Louisville, KY 40292, USA.
Payne
R S
RS
Reid
K H
KH
Tseng
M T
MT
Rigor
B M
BM
Schurr
A
A
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D004110:Diltiazem / Q000494:pharmacology*; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006323:Heart Arrest; D006624:Hippocampus / Q000098:blood supply / Q000166:cytology / Q000503:physiopathology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D009924:Organ Culture Techniques; D017966:Pyramidal Cells / Q000166:cytology / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D014665:Vasodilator Agents / Q000494:pharmacology*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D014665:Vasodilator Agents; D016291:Dizocilpine Maleate; D004110:Diltiazem