Protracted mild hypothermia provides long-term histological and behavioral protection following global cerebral ischemia

Colbourne, Frederick (1995) Protracted mild hypothermia provides long-term histological and behavioral protection following global cerebral ischemia. Doctoral (PhD) thesis, Memorial University of Newfoundland.

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Abstract

Global cerebral ischemia (cardiac arrest) often results in profound, but selective, hippocampal CAI injury. This cell death, which normally occurs hours to days later, induces profound anterograde amnesia in humans with habituation and working memory impairments in rodents. -- In this thesis, the gerbil model of global ischemia was used. Under Halothane anesthesia, both carotid arteries were isolated and briefly occluded. Without intervention, near-total CAI loss ensues with resultant memory impairments. -- In the first experiment a novel brain temperature system was compared to rectal and skull measurements. Brain temperature dropped during ischemia even though rectal and skull temperatures were maintained. Subsequently, prolonged Halothane anesthesia was found to enhance this dissociation. Thus, rectal and skull readings are not reliable indices of brain temperature during ischemia and anesthesia. Brain temperature must be controlled to avoid the confounding protective effects of intra-ischemic hypothermia. -- While the protective effects of mild intra-ischemic hypothermia are well documented, the value of postischemic cooling is less clear. Therefore, rigorous brain temperature measurement, lengthy survival times and behavioral tests were used to clarify the effects of postischemic hypothermia. Prolonged cooling (32°C for 12 hr) initiated 1 hour after normothermic ischemia was highly neuroprotective at 10 and 30 day survival against 3 minutes of ischemia, but provided only a mild, transient savings against a 5 minute episode. Habituation impairments, in open field tests, were also reduced in cooled gerbils. Notably, 24 hours of hypothermia initiated 1 hour after a 5 minute occlusion rescued almost all CAI neurons (90%) with 30 day survival. -- More recently, significant CAI savings were found with clear reductions in habituation (open field) and working memory (T-maze) impairments for up to 6 months postischemia (5 min) with 1 hour delayed hypothermia (32°C for 24 hr). While CAI protection at 6 months (-70%) was less than with 1 month survival it nonetheless showed effective and very persistent benefit. Hypothermia (32°C for 24 hr), when started 4 hours postischemia, saved ?12% of CAI cells at 6 months with mild behavioral benefit. Hypothermia (34°C from 1-25 hr postischemia) also reduced habituation impairments and rescued ?60% of CAI neurons with 1 month survival. -- In summary, these data indicate that delayed mild postischemic hypothermia is an efficacious and persistent neuroprotectant deserving of clinical investigation. -- [Key words: cerebral ischemia, postischemic hypothermia, open field, T-maze, CAI, delayed neuronal death]

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