Metabolic and Hemodynamic Activation of Postischemic Rat Brain by Cortical Spreading Depression

Abstract

Summary: Following transient ischemia of the brain, the coupling between somatosensory activation and the he modynamic-metabolic response is abolished for a certain period despite the partial recovery of somatosensory evoked responses. To determine whether this disturbance is due to alterations of the stimulus-induced neuronal ex citation or to a breakdown of the coupling mechanisms, cortical spreading depression was used as a metabolic stimulus in rats before and after ischemia. Adult rats were subjected to 30 min of global forebrain ischemia and 3-6 h of recirculation. EEG, cortical direct current (DC) po tential, and laser-Doppler flow were continuously re corded. Local CBF (LCBF), local CMR g lc (LCMR g1 c), regional tissue contents of ATP, glucose, and lactate, and regional pH were determined by quantitative autoradiog raphy, substrate-induced bioluminescence, and fluorom etry. Amplitude and frequency of the DC shifts did not differ between groups. In control animals, spreading de pression induced a 77% rise in cortical glucose consump tion, a 66% rise in lactate content, and a drop in tissue pH of 0.3 unit. ATP and glucose contents were not depleted.If cerebral global ischemia exceeds 10 min, long lasting impairment of neurological function will re sult. In the four-vessel occlusion model in rats that allows long-term survival after an ischemic impact, disturbances of sensorimotor integration and motor performance persist for at least 2 days (Combs and D' Alecy, 1987), although the supply of energy-rich phosphates is replenished within 1 h (Pulsinelli and Duffy, 1983;Naruse et al. , 1984).It has been suggested that despite the early re covery of energy metabolism, impaired neurologi- 564During the passage of DC shifts, transient increases «2 min) in laser-Doppler flow were observed, followed by a post-spreading depression hypoperfusion. A comparable although less expressed pattern of hemodynamic and metabolic changes was observed in the postischemic rats. Although baseline LCMR g lc was depressed after isch emia, it was activated 47% during spreading depression. Lactate increased by 26%, pH decreased by 0.3 unit, and ATP and glucose remained unchanged. The extent of the transient increase in laser-Doppler flow did not differ from that of the control group, and a post-spreading de pression hypoperfusion was also found. The results dem onstrate that the postischemic brain may, although to a lesser degree, cover additional energy demands. The pre viously observed suppression of functional activation af ter ischemia is probably caused by both alterations in afferent synaptic transmission and subsequent neuronal excitation and the diminution of the metabolic response to a local stimulus as observed during spreading depres sion.

Cortical Negative DC Deflections following Middle Cerebral Artery Occlusion and KCl-Induced Spreading Depression: Effect on Blood Flow, Tissue Oxygenation, and Electroencephalogram

“…In fact, spreading depression is an energy-requiring process that leads to substantial activation of energy-producing me tabolism. Measurements of cerebral metabolic rate of glucose carried out under similar conditions of repetitive spreading depression as in the present study revealed an increase by 77% (Kocher, 1990). Other authors reported a threefold increase in glu cose consumption (Gjedde et al, 1981) and a 45% rise of oxygen consumption (Mayevsky and Weiss, 1991).…”

“…Spreading depression substantially increases the metabolic rate to cope with the in creased workload of ion exchange pumps (Gjedde et aI., 1981). In the intact brain, this rise in meta bolic activity is coupled to the parallel increase of blood flow to ensure adequate oxygen delivery (Hansen et aI., 1980;Kocher, 1990). It is possible that this coupling is disturbed in the surroundings of the infarct and that this region suffers a period of relative hypoxia during the passage of each depo larization.…”

Repeated Negative DC Deflections in Rat Cortex following Middle Cerebral Artery Occlusion are Abolished by MK-801: Effect on Volume of Ischemic Injury

“…It is therefore possible that the tissue be comes transiently hypoxic during these episodes. This could explain why, in the present study, the duration of periinfarct DC deflections was as long as 10 min, i.e., much longer than the DC deflection during spreading depression in normal cortex, which lasts only �2 min (Mies and Paschen, 1984;Kocher, 1990). This observation is in line with an earlier study by Nedergaard and Astrup (1 986), who reported that DC deflections in the periinfarct area last for up to 8 min.…”

“…However, it is con ceivable that the combination of a marginal isch emia with repeated cell depolarizations creates a pathophysiological situation that may result in irre versible cell damage. In fact, in the intact animal, spreading depression is associated with an in creased metabolic rate for glucose (Shinohara et al , 1979), which is coupled to a similar rise in blood flow (Kocher, 1990;Mayevsky and Weiss, 1991 ). The increase in blood flow ensures adequate tissue oxygenation and is probably the main factor pre venting spreading depression from producing irre versible neuronal injury in normal animals (Neder gaard .…”

Uncoupled Cerebral Blood Flow and Metabolism after Severe Global Ischemia in Rats

“…(1988) demon strated uncoupling of CBF and CMR02 (hyperemia with an increase in CMRglc but not CMR02) even in the normal brain after peripheral nerve stimulation. Supporting the theory of coupling of CBF and me tabolism, measurements of CMRglc and CBF at 3 h after severe (30 min) GBI also showed concurrent hypoperfusion and hypometabolism with normal CBF/CMRglc (Ueki et aI., 1988;Kocher, 1990). Strongly supporting the theory of coupling of CBF and CMR02 during the postischemic hypoperfusion period, Michenfelder et aI.…”