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 hypot hermia (30 degrees C) has been shown to delay but not chronically prot ect the CA(1) hippocampus from transient global forebrain ischemia. Th e inability of a relatively short postischemic hypothermic period to p rotect chronically might involve a delayed or secondary injury mechani sm. 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 chronica lly protect histopathologically. Wistar rats underwent 10 min of normo thermic forebrain ischemia induced by bilateral common carotid artery occlusion plus hypotension (50 mg Hg). Four ischemia groups were studi ed after normothermic (37 degrees C) ischemia: no treatment; 3 h of im mediate postischemic hypothermia (30 degrees C); delayed MK-801 treatm ent (4 mg/kg) on postischemic days 3, 5, and 7; and postischemic hypot hermia combined with multiple MK-801 treatments. Two months after the ischemic insult, rats were perfusion-fixed for quantitative histopatho logical assessment. Postischemic hypothermia alone or MK-801 treatment alone failed to protect the CA(1) hippocampus chronically. However, i mmediate postischemic hypothermia combined with delayed MK-801 treatme nt led to significant increases in normal CA(1) neuron counts per micr oscopic field compared with normothermic ischemia. For example, neuron al counts within the hippocampal CA(1) areas were 58 +/- 39 (mean +/- SD) in normothermic ischemic rats compared with 395 +/- 198 in rats tr eated with postischemic hypothermia and MK-801, Chronic survival also led to pronounced striatal damage. Within the dorsolateral striatum, s ignificant protection was documented with either postischemic hypother mia alone or delayed MK-801 treatment alone. In the striatum, neuronal counts were 8 +/- 5, 47 +/- 29, and 63 +/- 30 in normothermic, MK-801 -treated, and postischemic hypothermic rats, respectively. Significant protection within the somatosensory cortex was not observed with any of the treatment protocols. These findings indicate that the postische mic hippocampus and striatum undergo a delayed excitotoxic insult as l ate as postischemic day 3. Based on chronic histopathological assessme nt, the therapeutic window for striatal neuroprotection after a brief global ischemic insult appears to be longer than previously appreciate d.