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

Abstract

Cortical spreading depression (CSD) is a transient depression of neuronal activity that spreads across the cortical surface. In the present studies, we have investigated 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 m M (mean ± SD). After 3 h, the extracellular [Ca2+] in the cortex (penumbral zone) was either normal (10/16 rats) or lowered to 0.5 m M (2/16 rats) or to 0.1 m M (4/16 rats). In the caudate nucleus (ischaemic core area), all rats had an extracellular [Ca2+] of ∼0.1 m M when measured after the 3 h recording period. Neuropathological evaluation of the brains of the animals, which had been allowed to survive for 24 h after MCA occlusion, revealed ischaemic damage in the dorsolateral cortex and caudate nucleus. Administration of the noncompetitive NMDA antagonist, MK-801 (3 mg/kg i.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 10 with a range of 0–2/rat) and the degree of decrease in extracellular [Ca2+] during CSDs (low level was 0.19 ± 0.15 m M, mean ± SD). Both the number of “small CSDs” and significantly the “big CSDs” were reduced by MK-801. The “small CSDs” were present in the border zone and also deeper within the infarct, whereas “big CSDs” and anoxic depolarisations only occurred closer to the infarct core. CSDs were not seen outside the border zone of the infarct. In conclusion, there was a good correlation between extracellular [Ca2+] changes and ischaemic damage in the infarcted 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.