REGIONAL ALTERATIONS OF PROTEIN-KINASE-C ACTIVITY FOLLOWING TRANSIENTCEREBRAL-ISCHEMIA - EFFECTS OF INTRAISCHEMIC BRAIN TEMPERATURE MODULATION

It is well established that ischemia-induced release of glutamate and the subsequent activation of postsynaptic glutamate receptors are impo rtant processes involved in the development of ischemic neuronal damag e. Moderate intraischemic hypothermia attenuates glutamate release and confers protection from ischemic damage, whereas mild intraischemic h yperthermia increases glutamate release and augments ischemic patholog y. As protein kinase C (PKC) is implicated in neurotransmitter release and glutamate receptor-mediated events, we evaluated the relationship between intraischemic brain temperature and PKC activity in brain reg ions known to be vulnerable or nonvulnerable to transient global ische mia. Twenty minutes of bilateral carotid artery occlusion plus hypoten sion were induced in rats in which intraischemic brain temperature was maintained at 30 degrees C, 37 degrees C, or 39 degrees C. Prior to a nd following ischemia, brain temperature was 37 degrees C in all group s. Cytosolic, membrane-bound, and total PKC activities were determined in hippocampal, striatal, cortical, and thalamic homogenates at the e nd of ischemia and at 0.25-24 h of recirculation. PKC activity of cont rol rats varied by region and were affected by altered brain temperatu re. For both membrane-bound and cytosolic PKC, there was a significant temperature effect, and for membrane-bound PKC there was also a signi ficant effect of region. Rats with normothermic ischemia (37 degrees C ) showed extensive depressions of all PKC fractions. Hippocampus and s triatum were noteworthy for depressions in PKC activity extending from the earliest (15 min) to the latest (24 h) recirculation times studie d, whereas cortex showed PKC depressions chiefly during the first hour of recirculation, and the thalamic pattern was inconsistent. In contr ast, in rats with hypothermic ischemia (30 degrees C), significant ove rall effects were noted only for total PKC in thalamus, which showed d epressed levels at both 1 and 24 h of recirculation. Rats with hyperth ermic (39 degrees C) ischemia also showed significant overall effects for the time course of membrane-bound, cytosolic, and total PKC activi ties in the hippocampus, striatum, and cortex. However, no significant reductions in PKC indices were observed in the thalamus. For membrane -bound PKC, significant temperature effects were noted for hippocampus , striatum, and cortex, but not for thalamus. For cytosolic, as well a s total PKC, activity, significant temperature effects were noted for all four brain regions. Our results indicate that ischemia, followed b y reperfusion, induces a significant reduction in PKC activity and tha t this process is highly influenced by the brain temperature during is chemia. Furthermore, our data also establish that differences exist in the response of PKC to ischemia/recirculation in vulnerable versus no nvulnerable brain regions. These results suggest that PKC alterations may be an important factor involved in the modulatory effects of tempe rature on the outcome following transient global ischemia.