Summary: The objective of this study was to define the degree of hypothermia required to diminish ischemic in jury to CAl hippocampal neurons following 5-min bilat eral ischemia in the gerbiL The temperature of the body and head was regulated in three groups of animals at 37.5, 35.5, or 32SC during 5-min bilateral carotid artery oc clusion. Upon recirculation, normothermia was restored in all animals, and recovery was permitted for 1 week. Ischemic injury to CAl hippocampus was determined us ing three endpoints: histologic injury, ATP content, and adenylate kinase activity. Reduction of head temperature to 35.5 and 32SC during ischemia diminished histologic injury and improved CAl levels of ATP and adenylate kinase activity in a dose-dependent manner. Indeed, Transient bilateral cerebral ischemia in the gerbil is a model frequently used to evaluate pharmaco logic protection against ischemic injury. For exam ple, antagonists of N-methyl-o-aspartate receptors (Gill et aI., 1987) or of voltage-sensitive calcium channels (Alps et aI., 1988) have been reported to reduce the extent of ischemic injury to CAl pyra midal cells in gerbil hippocampus, However, in small rodents such as gerbils, body and brain tem perature may change rapidly in response to anes thesia or administration of pharmacologic agents. Thus, unless brain temperature is carefully con trolled, cellular protection could easily result from drug-induced hypothermia rather than specific pharmacologic antagonism. Indeed, there have been reports that the N-methyl-o-aspartate antago nist MK-801 failed to protect CAl neurons in gerbil Received October 3, 1989; revised December 28, 1989 55732SC completely abolished ischemic injury to CAl hip pocampus, judging from each of the three endpoints. Re duction of head temperature to 32SC delayed but did not prevent the depletion of ATP throughout the hippocam pus during the 5-min ischemic insult. These results dem onstrate that a decrease in head temperature of only 2°C reduces the degree of CAl injury in the gerbil model of 5-min bilateral ischemia. Thus, it is imperative to main tain strict normothermia in pharmacologic studies of isch emic protection. Finally, administration of nicardipine to normothermic gerbils failed to diminish ischemic injury in the CAl hippocampus. Key Words: Adenosine triphos phate-Hippocampus-Hypothermia-Ischemia Nicardipine.hippocampus when hypothermia was avoided (Buchan and Pulsinelli, 1989;Nowak, 1989).Recently, it has been recognized that minor de grees of hypothermia have a profound effect on the severity of ischemic injury. Thus, even a laC de crease of body temperature reduced the alteration of energy metabolites in hypoxic-ischemic rat brain (Berntman et aI., 1981). Further, a reduction of brain temperature of 2°C during 20-min forebrain ischemia in the rat significantly diminished the ex tent of neuronal injury (Busto et aI., 1987). Despite the important influence of brain temperature on ischemic damage, a systematic study of mild hypo thermia in the gerbil model of bilateral i...
Brain levels of NADH and NAD+ were measured in three models of cerebral ischemia to determine whether degradation of the pyridine nucleotides is enhanced in models that generate high concentrations of lactic acid. Complete ischemia (decapitation), in which lactate increased to 14 mmol/kg, caused a gradual decrease in the NAD pool to 50% of control by 2 h. During focal ischemia (occlusion of the middle cerebral artery), the decrease in the NAD pool was less pronounced (82% of control at 2 h) despite the accentuated accumulation of lactate to 33 mmol/kg. In a third model (unilateral hypoxia-ischemia), pretreatment of animals with glucose augmented the ischemic elevation of lactate from 30 mmol/kg to 40 mmol/kg and greatly impaired restoration of energy metabolites during recirculation. However, glucose pretreatment had no effect on the size of the NAD pool during ischemia or early recovery. These results, therefore, demonstrate that the pyridine nucleotide pool is not rapidly degraded during ischemic insults that accumulate high concentrations of lactic acid. The stability of the NAD pool may have been enhanced by the limited increase in brain levels of NADH that occurred in these models of incomplete ischemia.
Summary: Transient focal ischemia was produced in rat brain using simultaneous, reversible occlusion of the mid dle cerebral artery (MCA) and both carotid arteries. NADH tissue fluorescence and regional levels of ATP and lactate were measured after occlusion for 1 or 2.5 h and after reperfusion for 1 or 24 h following a 2.5-h insult. Occlusion for 1 or 2.5 h caused a marked but microhet erogenous increase in NADH fluorescence, which was restricted to the MCA territory of the ipsilateral cortex. In this ischemic core, tissue levels of ATP were nearly depleted, while lactate accumulated to 10-13 mmoUkg. Metabolic alterations were less pronounced in regions ad jacent to the ischemic core; however, one border region experienced a progressive increase in lactate between 1In recent years, several models of focal ischemia in rat brain have been developed employing middle cerebral artery (MCA) occlusion (Tamura et aI., 1981 ; Shigeno et aI., 1985;Chen et al., 1986; Brint et aI., 1988). Although regional blood flow and histo pathology have been well documented in these models, less is known about focal alterations of en ergy metabolites. Proximal occlusion of the MCA alone was reported to decrease ATP by 18% in pa rietal cortex and 46% in striatum by 2 h, with fur ther decreases occurring by 48 h (Nowicki et aI., 1988). In this study, however, regional information was limited by the large size (40 mg) of the areas analyzed. Micromethods have been used to demon strate near depletion of energy metabolites in the ischemic core following proximal MCA occlusion (Selman et aI., 1987). However, the anatomic vari ability of the ischemic core in this model required the use of a perfusion indicator in each animal.Received June 25, 1990; revised September 28, 1990; accepted October 2, 1990.Address correspondence and reprint requests to Dr. F. A. Welsh at 313 Medical Education Bldg., 36th and Hamilton Walk, Philadelphia, PA 19104-6070, U.S.A.Abbreviation used: MeA, middle cerebral artery. 459and 2.5 h. NADH fluorescence and metabolite levels were not significantly altered in subcortical structures. In animals reperfused after a 2.5-h insult, NADH fluores cence diminished in the ischemic core to abnormally low levels, ATP was restored only to 37-50% of control, and lactate remained elevated. By 24 h, histologic infarction was evident in the regions with metabolic impairment. These results indicate that focal depletion of energy me tabolites for 2.5 h caused irreversible impairment of en ergy metabolism and focal infarction even though lactate accumulation was moderate. Key Words: ATP-Focal ischemia-Lactate-Middle cerebral artery-NADH flu orescence-Regional metabolites.Reproducible infarction in the cerebral cortex has been reported in models of distal MCA occlusion combined either with bilateral carotid artery occlu sion (Chen et aI., 1986) or with ipsilateral carotid occlusion in spontaneously hypertensive rats (Brint et aI., 1988). Regional studies of metabolic alter ation in these models of distal MCA occlusion have not been...
Unilateral cerebral hypoxia-oligemia was produced in anesthetized mice using carotid artery occlusion combined with systemic hypoxia (10% O2). In the cerebral cortex ipsilateral to the carotid occlusion, ATP levels were depleted during a 30-min insult, but were restored to 64% of control during 60 min of recovery. Pretreatment of animals with glucose diminished the restoration of ATP in a dose-dependent manner. Thus, when blood glucose levels exceeded 12-13 mM (225 mg/dl), ATP recovery was greatly impaired. Neither galactose nor 3-O-methylglucose mimicked the detrimental effect of glucose. However, pretreatment with mannose, which is readily metabolized by brain, impaired restoration of ATP. The impairment, therefore, appears to be specific for substrates of cerebral metabolism. The ischemic accumulation of lactate in the ipsilateral cortex was augmented by only 30% at blood glucose levels well above the threshold for ATP recovery. Thus, unless recovery of energy metabolism is sensitive to small increments in brain lactate, it is difficult to explain the glucose-induced energy failure on the basis of enhanced lactic acidosis. Ipsilateral cerebral blood flow (CBF), measured with [14C]iodoantipyrine during hypoxia and recovery, was lower in glucose-pretreated than in saline-pretreated animals. However, the poor correlation between CBF and ATP, measured in the same tissue samples at 15 min recovery, failed to substantiate that regeneration of ATP was flow-limited early in recovery.
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