Induction of spreading depression in the ischemic hemisphere following experimental middle cerebral artery occlusion: effect on infarct morphology

Abstract

This study was undertaken to test whether transient depolarizations occurring in periinfarct regions are important in contributing to infarct spread and maturation. Following middle cerebral artery (MCA) occlusion we stimulated the ischemic penumbra with recurrent waves of spreading depression (SD) and correlated the histopathological changes with the electrophysiological recordings. Halothane-anesthetized, artificially ventilated Sprague-Dawley rats underwent repetitive stimulation of SD in intact brain (Group 1; n = 8) or photothrombotic MCA occlusion coupled with ipsilateral common carotid artery occlusion (Groups 2 and 3, n = 9 each). The electroencephalogram and direct current (DC) potential were recorded for 3 h in the parietal cortex, which represented the periinffarct border zone in ischemic rats. In Group 2, only spontaneously occurring negative DC shifts occurred; in Group 3, the (nonischemic) frontal pole of the ischemic hemisphere was electrically stimulated to increase the frequency of periinfarct DC shifts. Animals underwent perfusion-fixation 24 h later, and volumes of complete infarction and scattered neuronal injury ("incomplete infarction") were assessed on stained coronal sections by quantitative planimetry. Electrical induction of SD in Group 1 did not cause morphological injury. During the initial 3 h following MCA occlusion, the number of spontaneous periinfarct depolarization in Group 2 (7.0 +/- 1.5 DC shifts) was doubled in Group 3 by frontal current application (13.4 +/- 2.7 DC shifts; p < 0.001). The duration as well as the integrated negative amplitude of DC shifts over time were significantly greater in Group 3 than in Group 2 rats (duration, 5.7 +/- 3.8 vs. 4.1 +/- 2.5 min; p < 0.05). Histopathological examination disclosed well-defined areas of pannecrosis surrounded by a cortical rim exhibiting selectively damaged acidophilic neurons and astrocytic swelling in otherwise normal-appearing brain. Induction of SD in the ischemic hemisphere led to a significant increase in the volume of incomplete infarction (19.0 +/- 6.1 mm3 in Group 3 vs. 10.3 +/- 5.1 mm3 in Group 2; p < 0.01) and of total ischemic injury (100.7 +/- 41.0 mm3 in Group 3 vs. 66.5 +/- 24.7 mm3 in Group 2; p < 0.05). The integrated magnitude of DC negativity per experiment correlated significantly with the volume of total ischemic injury (r = 0.780, p < 0.0001). Thus, induction of SD in the ischemic hemisphere accentuated the development of scattered neuronal injury and increased the volume of total ischemic injury. This observation may be explained by the fact that with limited perfusion reserve, periinfarct depolarization are associated with episodic energy failure in the acute ischemic penumbra.