Effect of delayed MK-801 (dizocilpine) treatment with or without immediate postischemic hypothermia on chronic neuronal survival after global forebrain ischemia in rats.
In contrast to intraischemic hypothermia, immediate postischemic hypothermia (30 degrees C) has been shown to delay but not chronically protect the CA1 hippocampus from transient global forebrain ischemia. The inability of a relatively short postischemic hypothermic period to protect chronically might involve a delayed or secondary injury mechanism. We determined whether delayed treatment with the noncompetitive N-methyl-D-aspartate receptor antagonist MK-801 (dizocilpine), alone or in combination with immediate postischemic hypothermia, would chronically protect histopathologically. Wistar rats underwent 10 min of normothermic forebrain ischemia induced by bilateral common carotid artery occlusion plus hypotension (50 mg Hg). Four ischemia groups were studied after normothermic (37 degrees C) ischemia: no treatment; 3 h of immediate postischemic hypothermia (30 degrees C); delayed MK-801 treatment (4 mg/kg) on postischemic days 3, 5, and 7; and postischemic hypothermia combined with multiple MK-801 treatments. Two months after the ischemic insult, rats were perfusion-fixed for quantitative histopathological assessment. Postischemic hypothermia alone or MK-801 treatment alone failed to protect the CA1 hippocampus chronically. However, immediate postischemic hypothermia combined with delayed MK-801 treatment led to significant increases in normal CA1 neuron counts per microscopic field compared with normothermic ischemia. For example, neuronal counts within the hippocampal CA1 areas were 58 +/- 39 (mean +/- SD) in normothermic ischemic rats compared with 395 +/- 198 in rats treated with postischemic hypothermia and MK-801. Chronic survival also led to pronounced striatal damage. Within the dorsolateral striatum, significant protection was documented with either postischemic hypothermia alone or delayed MK-801 treatment alone.
Dietrich
W D
WD
Department of Neurology, University of Miami, School of Medicine, Florida 33101, USA.
Lin
B
B
Globus
M Y
MY
Green
E J
EJ
Ginsberg
M D
MD
Busto
R
R
D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000628:therapy*; D002452:Cell Count / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D007036:Hypothermia, Induced; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D016548:Prosencephalon / Q000098:blood supply*; D051381:Rats; D017208:Rats, Wistar
D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate