Potassium-Induced Cortical Spreading Depressions during Focal Cerebral Ischemia in Rats: Contribution to Lesion Growth Assessed by Diffusion-Weighted NMR and Biochemical Imaging

Abstract

Summary: In focal ischemia of rats, the volume of ischemic lesion correlates with the number of peri-infarct depolariza tions, To test the hypothesis that depolarizations accelerate in farct growth, we combined focal ischemia with externally evoked spreading depression (SD) waves, Ischemic brain in farcts were produced in halothane-anaesthetized rats by intra luminal thread occlusion of the middle cerebral artery (MCA), In one group of animals, repeated SDs were evoked at IS-min intervals by microinjections of potassium acetate into the fron tal cortex, In another group, the spread of the potassium-evoked depolarizations was prevented by application of the N-methyl D-aspartate (NMDA) receptor antagonist dizocilpine (MK-80 I), The volume of ischemic lesion was monitored for 2 h by diffusion-weighted imaging (DWI) and correlated with electro physiological recordings and biochemical imaging techniques, In untreated rats, each microinjection produced an SD wave and a stepwise rise of the volume and signal intensity of the In focal cerebral ischemia of rat infarct size correlates with the number of peri-infarct spreading depression (SD)-like depolarizations (Mies et aI., 1993; Chen et aI., 1993). These depolarizations are generated in the border zone of the ischemic lesion and spread into the peri infarct surrounding (Nedergaard and Hansen, 1993; Ne dergaard and Astrup, 1986). Glutamate antagonists such as dizocilpine (MK-801) or 2,3-dihydroxy-6-nitro-7-Received January I L 1996; final received May 3. 1996; accepted May 29, 1996.Address correspondence. and reprint requests to Prof. Dr. K.-A. Hossmann, Max-Planck-Institut fUr neurologische Forschung. Gleuelerstrasse 50, D-50931 Kiiln, FR Germany.Abbreviations used: ADC, apparent diffusion coefficient; ANOY A. analysis of variance; DC, direct current; DWl, diffusion-weighted im aging; MCA, middle carotid artery; MR, magnetic resonance; NBQX, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F)-quinoxaline; NMDA, N methyl-D-aspartate; RF, radiofrequency; ROI, region of interest; SD, spreading depression; TE. spin echo. 1090DWI-visible cortical lesion, The volume of this lesion in creased between IS min and 2 h of MCA occlusion from 19 ± 15% to 66 ± 16% of ipsilateral cortex, In dizocilpine-treated animals, microinjections of potassium did not evoke SDs, nor did the volume and signal intensity of the DWI-visible cortical lesion change, At 15 min after MCA occlusion, the DWI visible lesion was larger than in untreated animals-43 ± 16% of the ipsilateral cortex; however, after 2 h, it increased only slightly further to 49 ± 21 %. Slower lesion growth in the ab sence of SDs was also reflected by the volume of ATP-depleted tissue, which, after 2 h of MCA occlusion, involved 26 ± 12% of the ipsilateral cortex in treated and 49 ± 9% in untreated animals (p < 0.(1). These observations support the hypothesis that peri-infarct depolarizations accelerate cerebral infarct growth.

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

“…A downward trend in glucose concentration is maintained at 3 h ( þ : 180 versus 20 mins, t (paired) ¼ 3.075, P ¼ 0.0133), whereas lactate appears more stable. (Takano et al, 1996;Busch et al, 1996;Back et al, 1996), and do so incrementally (because infarct size is proportional to the number of PIDs; Mies et al, 1993).…”

“…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). A role for PIDs as a cause rather than simply as a marker of the progression of infarct growth has been indicated by the positive correlation between number of PID events and infarct size (Gill et al, 1992;Chen et al, 1993;Mies et al, 1993) and, critically, by the demonstration that induction of depolarisations within or adjacent to the penumbra can enlarge the infarct (Back et al, 1996;Busch et al, 1996;Takano et al, 1996).…”

Dynamic Changes in Brain Glucose and Lactate in Pericontusional Areas of the Human Cerebral Cortex, Monitored with Rapid Sampling On-Line Microdialysis: Relationship with Depolarisation-Like Events

“…Second, studies of the effects of MCAO in several animal models of stroke have repeatedly yielded evidence of spontaneous events with electrophysiological features similar to those of CSD, but, probably unlike CSD, with proven capacity to augment ischemic damage-PIDs (Back et al, 1996;Busch et al, 1996;Takano et al, 1996). The potential contribution of depolarisation events spreading in the injured cerebral cortex to adverse outcome from acute brain injury in humans is discussed in a review (Strong and Dardis, 2005).…”

“…The proposed mechanism of damage in focal cerebral cortical ischaemia-amounting to maturation or extension of infarction into the penumbrahas been reviewed by Hossmann (1996). Nedergaard and Astrup (1986) emphasised the likelihood of tissue glycopenia in association with PIDs, and application of our method to monitor glucose and lactate concentrations in dialysate from peri-infarct cortex after permanent (experimental) MCAO has demonstrated transient, coupled reductions in glucose and increases in lactate linked to PIDs, and occurring on a background of progressive depletion of the extracellular glucose pool (Hopwood et al, in press).…”

“…Subsequently, we applied the method in perilesion cerebral cortex in patients requiring emergency craniotomy for traumatic or spontaneous intracerebral haematoma. Specifically, we reasoned that since peri-infarct depolarisations (PIDs) are a prominent feature of the penumbra in experimental MCAO in non-human primates (Branston et al, 1977;Strong et al, 2000), in the cat (Saito et al, 1995;Strong et al, 1983) and in the rat (Gill et al, 1992;Iijima et al, 1992;Nedergaard and Astrup, 1986) and contribute to its gradual recruitment into the core territory (Back et al, 1996;Busch et al, 1996;Takano et al, 1996), we should first apply rsMD experimentally to characterise the time course of dialysate glucose and lactate in the penumbra, with special reference to PIDs. In this report, we describe our subsequent experience with the application of the same method in 11 patients, with the aim of rapidly and automatically acquiring glucose and lactate time series data for two purposes.…”