BIOCHEMICAL RESPONSES OF THE FOREBRAIN TO ISCHEMIA (CEREBRAL, STROKE, CYCLIC NUCLEOTIDES)

This investigation examined the effect of episodes of ischemia and reperfusion on the activity of ion-specific ATPase enzymes and enzymes involved in cyclic nucleotide metabolism, i.e., adenylate cyclase, guanylate cyclase and cyclic AMP phosphodiesterase. A model of global cerebral ischemia (bilateral telencephalic ischemia) and a model of focal cerebral infarction and edema (unilateral telencephalic ischemia) in the gerbil (Meriones unguiculatus) were characterized with regard to enzymatic alterations, regional vulnerability, effect of several anesthetic agents and the length of the ischemic and/or recirculation period. Changes in susceptible enzymes were then used to monitor the effects of putative therapeutic agents.; The activity attributed to components of the adenylate cyclase system (hormone receptor, transducer or guanine nucleotide binding site, and catalytic site) were assessed in homogenates of various brain regions. Deficits in adenylate cyclase depended on the duration of recirculation of the tissue following 60 min of ischemia. Damage to catecholamine-, GTP-, or forskolin-activated adenylate cyclase was present to varying degrees in the frontal cortex, hippocampus and olfactory tubercle, but not in the nucleus accumbens or olfactory bulb.; The effect of secondary ischemia (or damage occurring as a secondary change when blood flow is returned to the tissue) on cyclic nucleotide levels was examined in regions of rapidly fixed gerbil brains (in situ microwave irradiation). Levels of cyclic AMP rose after a secondary ischemic episode. Cyclic GMP concentrations were unchanged.; The activity of Na('+), K('+)-responsive ATPase was depressed by a secondary ischemic ictus (60 min plus 30 min reflow) in the frontal cortex, hippocampus, striatum and thalamus, but not in the hypothalamus and olfactory bulb.; Temporal alterations in histopathology and enzymatic activity were assessed in various brain regions after prolonged unilateral carotid occlusion. A correlation was found between the degree of histological changes and deficits in adenylate cyclase responsiveness.; Two calcium antagonists were assessed for ability to alter the damage to Na('+), K('+)-ATPase and measurements of hormone-responsive adenylate cyclase incurred after a secondary ischemic insult (60 min plus 40 min reflow).; These investigations suggest that ischemia and the consequent reperfusion of the tissue alters cellular membranes and affects membrane proteins dependent on a particular phospholipid environment for normal activity. (Abstract shortened with permission of author.)...