Factors Influencing the Frequency of Fluorescence Transients as Markers of Peri-Infarct Depolarizations in Focal Cerebral Ischemia

Abstract

Background and Purpose-Peri-infarct depolarizations (PIDs) that occur in ischemic boundary zones of the cerebral cortex of experimental animals have been shown to promote rather than simply to indicate the evolution of the lesion and are especially prominent in the rat. To study the influence of one factor, species, on PID incidence, we compared the frequency of PIDs in a primate species, the squirrel monkey, with that in the cat after middle cerebral artery occlusion. Plasma glucose was reviewed as a possible cause of interexperiment variability in the cat experiments. Methods-In open-skull experiments under chloralose anesthesia, changes in cortical fluorescence believed to indicate NADH/NAD ϩ redox state, as markers of PIDs, were recorded by serial imaging of the cortical surface in vivo for 4 hours after middle cerebral artery occlusion. Results-Fluorescence transients occurred in squirrel monkeys at a frequency (meanϮSD) of 0.7Ϯ0.8 hours Ϫ1 (nϭ5), which was not significantly less than in that observed in cats (1.3Ϯ1.6 hours Ϫ1 , nϭ8). Data from the cat experiments indicated a relationship between number of transients (dependent) and plasma glucose, with a striking increase in PID frequency in association with values of mean postocclusion plasma glucose Ͻ4.1 mmol/L (Mann-Whitney Uϭ15.0, Pϭ0.034); this observation agrees well with other published findings. Conclusions-Transient changes in fluorescence strongly suggestive of peri-infarct depolarizations, either transient or terminal, occur and propagate in the ischemic cerebral cortex of a nonhuman primate. The results also suggest that the relationship of frequency of peri-infarct depolarizations with plasma glucose requires further examination, to confirm the finding and to determine a safe lower limit for a target range for control of plasma glucose if insulin is used in the management of patients with cerebral ischemia. (Stroke. 2000;31:214-222.)

Glucose Modulation of Spreading Depression Susceptibility

“…In another study, hypoglycemia (o75 mg/dL) was associated with higher frequency of peri-infarct SDs in cats. 10 Although in our study hypoglycemia did not appear to enhance SD susceptibility in nonischemic brain, it is possible that depleted glucose pool makes ischemic penumbra more sensitive to hypoglycemia to facilitate peri-infarct SD occurrence. We did not observe spontaneous SD events analogous to anoxic depolarization in any of the hypoglycemic animals, 28 but hypoglycemia did delay SD recovery as blood glucose levels were generally below 50 mg/dL.…”

“…[7][8][9] Indeed, hyperglycemia suppresses peri-infarct SDs. [10][11][12] However, it is not clear whether this is because of improved energy status in ischemic penumbra stabilizing the polarization state, or because tissue glucose availability directly modulates SD susceptibility. In support of the latter, hypoglycemia appears to lower topical KCl concentrations required to trigger a SD, 13 and hyperglycemia has been reported to markedly reduce the amplitude of KCl-induced SDs.…”

Transient Changes in Cortical Glucose and Lactate Levels Associated with Peri-Infarct Depolarisations, Studied with Rapid-Sampling Microdialysis

“…They also reported a high cerebral glucose utilisation rate in this territory, and inferred that the cortical free glucose pool would be highly labile, and perhaps totally depleted under these conditions. In support of these findings, a study of the frequency of spontaneous PIDs after MCAO in the cat found serendipitously that this increased at mean postocclusion plasma glucose levels of less than some 4.5 mmol/L (Strong et al, 2000). The apparent dependence of PID frequency on plasma glucose was interpreted (on the assumptions that anaerobic glycolysis had become established in the penumbra and that the astrocytic glycogen pool had been exhausted) as indicating that maintenance of ion/excitatory-neurotransmitter homostasis becomes critically dependent on glucose availability from residual perfusion.…”

“…It is therefore important to understand the metabolic features and consequences of PIDs, and to apply this knowledge and, where appropriate, the technology that underpins it, in the study and management of acute injury to the human brain. Nedergaard and Astrup (1986) drew attention to the likelihood of extreme glycopenia developing in the ischaemic penumbra, and we had recently found serendipitously that only a mild reduction in plasma glucose might be required to elicit an increase in PID frequency (Strong et al, 2000). Under these particular conditions, the possibility of a vicious circle would arise, in which PIDs deplete the residual tissue glucose pool, hence increasing the probability of further PIDs.…”

“…Recurrent, spontaneous depolarisations occur and propagate in the penumbra in a number of species including non-human primates (Branston et al, 1977;Strong et al, 2000), cat (Strong et al, 1983;Saito et al, 1995), and the rat (Nedergaard and Astrup, 1986;Gill et al, 1992;Iijima et al, 1992). These events-periinfarct depolarisations (PIDs)-appear to arise principally at the edge of the core area and spread into the peri-infarct zone (Strong et al, 1996).…”