Hyperthermia enhances spectrin breakdown in transient focal cerebral ischemia.
Calpain-mediated spectrin degradation is triggered by cerebral ischemia and, when persistent, is thought to signal irreversible neuronal injury. Hyperthermia superimposed upon cerebral ischemia may exacerbate the injury process. In this study, we compared the extent of spectrin degradation in the brains of rats subjected to 1 h of transient proximal middle cerebral artery (MCA) clip-occlusion performed under conditions of cranial normothermia (37 degrees C) or mild cranial hyperthermia (39 degrees C). Immunocytochemical localization of spectrin breakdown products was achieved by the use of a rabbit polyclonal antibody which reacted selectively with calpain-generated fragments of brain spectrin. The perfusion times studied were 1, 4 or 24 h. Following normothermic MCA occlusion, spectrin immunoreactivity was present only occasionally and only in scattered cortical neurons immediately upon reperfusion and 1 h later; all normothermic brains showed space immunoreactivity at 4 h of reperfusion; and no immunoreactivity was detected at 24 h. By contrast, following hyperthermic MCA occlusion, moderate-to-intense immunostaining was present in cortical pyramidal neurons even immediately upon reperfusion and persisted at 1 h of reperfusion. At 4 and 24 h, most brains exhibited dense immunoreactivity associated with morphologically shrunken neurons. Following 24 h survival, semi-thick plastic sections revealed intact neuropil and only selective neuronal necrosis in normothermic rats. By contrast, pan-necrosis was evident 24 h after the hyperthermic ischemic insult. These results indicate that mild cranial hyperthermia superimposed upon transient focal ischemia markedly enhances calpain activation and spectrin degradation; this process appears to be an important mechanism by which hyperthermia exacerbates ischemic injury.
Morimoto
T
T
Department of Neurology, University of Miami School of Medicine, FL 33101, USA.
Ginsberg
M D
MD
Dietrich
W D
WD
Zhao
W
W
D000818:Animals; D001157:Arterial Occlusive Diseases / Q000378:metabolism; D001921:Brain / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism; D001923:Brain Chemistry; D002154:Calpain / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D005334:Fever / Q000378:metabolism*; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000378:metabolism*; D013049:Spectrin / Q000378:metabolism*; D014048:Tolonium Chloride
D013049:Spectrin; D014048:Tolonium Chloride; D002154:Calpain