The Effect of MK-801 on Cortical Spreading Depression in the Penumbral Zone following Focal Ischaemia in the Rat

Abstract

Summary: Cortical spreading depression (CSD) is a tran sient depression of neuronal activity that spreads across the cortical surface. In the present studies, we have in vestigated CSD activity in the penumbral zone following permanent middle cerebral artery (MCA) occlusion in the rat (n = 16/group), using double-barreled Ca2+ -sensitive microelectrodes. Measurements of CSD activity were made for 3 h in each animal. During this time, a varying number of spontaneous CSDs were seen in the control group (total was 30, with a range of 0-7/rat). These CSDs were of varying duration: "small" (-1 min) and "big" (5-45 min) CSDs. During a CSD, the extracellular [Ca2+] decreased to 0.11 ± 0.07 mM (mean ± SD). After 3 h, the extracellular [Ca2+] in the cortex (penumbral zone) was either normal (10/16 rats) or lowered to 0.5 mM (2/16 rats) or to 0.1 mM (4/16 rats). In the caudate nucleus (isch aemic core area), all rats had an extracellular [Ca2 +] of -0.1 mM when measured after the 3 h recording period. Neuropathological evaluation of the brains of the ani mals, which had been allowed to survive for 24 h after MCA occlusion, revealed ischaemic damage in the dor solateral cortex and caudate nucleus. Administration of the noncompetitive NMDA antagonist, MK-801 (3 mglkgThe excitatory amino acid neurotransmitter L-glutamate is thought to be involved in the neuro nal degeneration that is seen following a period of cerebral ischaemia (Meldrum, 1985;Rothman and Olney, 1986;Choi, 1988 Abbreviations used: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid; ANOV A. analysis of vari ance; CSD, cortical spreading depression; MCA, middle cerebral artery; NMDA, N-methyl-D-aspartate. 371i.p.), 30 min after MCA occlusion resulted in 24 and 29% reductions in the volume of hemispheric and cortical damage, respectively, which was highly significant (p < 0.0001); no protection was seen against caudate damage.MK-801 also significantly (p < 0.05) reduced the number of CSDs (total was IO with a range of 0-2/rat) and the degree of decrease in extracellular [Ca2+] during CSDs (low level was 0.19 ± 0.15 mM, mean ± SD). Both the number of "small CSDs" and significantly the "big CSDs" were reduced by MK-80l. The "small CSDs" were present in the border zone and also deeper within the infarct, whereas "big CSDs" and anoxic depolarisa tions only occurred closer to the infarct core. CSDs were not seen outside the border zone of the infarct. In con clusion, there was a good correlation between extracel lular [Ca2+] changes and ischaemic damage in the inf arcted region following MCA occlusion. MK-801 reduced the ischaemic damage in the penumbral zone in parallel with attentuation of the number and amplitude of CSDs and thereby a reduced intracellular Ca2 + overload. Key Words: Cerebral ischaemia-MK-801-Spreading depres sion-Glutamate-NMDA. Harreveld (1959), who showed that cortical spread ing depression (CSD) could be produced in rabbits by applying glutamate to the cortical surface and proposed that this was related to neuronal hypoxia. Further ev...

Spreading Waves of a Reduced Diffusion Coefficient of Water in Normal and Ischemic Rat Brain

“…The fre quency varies with experimental conditions such as the method of the vascular occlusion, craniectomy, electrode insertion, anesthesia, brain temperature, blood glucose level, etc. Previous studies demon strated that 5-10 spontaneous depolarizations could be recorded during the first few hours after the oc clusion (Gill et al, 1992;Iijima et al, 1992;Neder gaard and Hansen, 1993;Back et al, 1994;Dietrich et al, 1994). We observed transient ADC changes outside of the ischemic lesion in 3 of 12 animals with MCA occlusion (25%).…”

“…SD or SD-like depolarizations occur in the ipsi lateral cortex after MCA occlusion in rats (Gill et al, 1992;Iijima et al, 1992;Nedergaard and Hansen, 1993;Bak et al, 1994;Dietrich et al, 1994), as measured electrophysiologically. The fre quency varies with experimental conditions such as the method of the vascular occlusion, craniectomy, electrode insertion, anesthesia, brain temperature, blood glucose level, etc.…”

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

“…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).…”

“…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).…”

Photothrombotic Infarction Triggers Multiple Episodes of Cortical Spreading Depression in Distant Brain Regions

“…After middle cerebral artery occlusion (M CAo) in rats, for example, time-dependent heterogeneous changes in glucose consumption and cerebral blood flow (CBF) were recorded within the infarct rim (Nedergaard and Astrup, 1986;Shiraishi et al, 1989). Also, transient events occurred at the periphery of the infarct zone after MCAo in rat (Nedergaard and Astrup, 1986;Gill et al, 1992;Iijima et al, 1992) which resemble cortical spreading depression (CSD) (Leao, 1944). Similar events were recorded in other models of focal isch emia (Branston et al, 1977;Harris et aI., 1981;Strong et al, 1983).…”