Temporal ordering of pathogenic events following transient global ischemia

• Published in: Brain research Vol. 790; no. 1; pp. 1 - 13
• Main Authors: Bartus, Raymond T., Dean, Reginald L., Mennerick, Steve, Eveleth, David, Lynch, Gary
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 20-04-1998; Amsterdam Elsevier; New York, NY
• Subjects: Animals; Biological and medical sciences; Brain Chemistry - physiology; Calpain - metabolism; Calpain proteolysis; Cell Death - physiology; Cytoskeleton; Cytoskeleton - physiology; Delayed cell death; Excitatory Postsynaptic Potentials - physiology; Field potentials; Hippocampus; Hippocampus - cytology; Hippocampus - enzymology; Hippocampus - physiopathology; Ischemic Attack, Transient - metabolism; Ischemic Attack, Transient - physiopathology; Medical sciences; Neurology; Neurons - cytology; Neurons - enzymology; Rats; Rats, Sprague-Dawley; Selective vulnerability; Silver stain; Silver Staining; Spectrin; Spectrin - analysis; Time Factors; Vascular diseases and vascular malformations of the nervous system; Spectrin; Delayed cell death; Calpain proteolysis; Selective vulnerability; Cytoskeleton; Field potentials; Silver stain; Hippocampus; Rat; Pathogenesis; Cysteine endopeptidases; Central nervous system; Cardiovascular disease; Vascular disease; Ischemia; Proteolysis; Pyramidal neuron; Cerebrovascular disease; Nervous system diseases; Enzyme; Rodentia; Calpain; Transitory; Cerebral disorder; Peptidases; Vertebrata; Experimental disease; Mammalia; Animal; Central nervous system disease; Temporal study; Hydrolases; Brain (vertebrata)
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(97)01414-5

Rats were subjected to transient global ischemia (four vessel occlusion) and time-related changes in the selectively vulnerable hippocampal field CA1 were characterized. The assessment included ex vivo field responses to afferent stimulation, silver staining, calpain-induced spectrin breakdown, chromatolysis, and cell death, beginning at 6 h post-ischemia and continuing until total disintegration of the pyramidal cells occurred several days later. The earliest change observed was a modest increase in the slope and amplitude of field CA1 potentials (at 6 h). The hyperresponsiveness was most apparent at higher stimulation currents and persisted unchanged at 16 h post-ischemia. Three effects became detectable within 24 h, post-ischemia: (a) an increase in concentrations of calpain-mediated, spectrin breakdown products; (b) enhanced silver staining in the deep pyramidal neurons of the field CA1 with lesser, though still apparent, staining of stratum radiatum, and (c) a decrease in amplitude and slope of field CA1 responses to afferent stimulation. Both the concentration of spectrin breakdown products and the intensity of silver staining progressively increased to a maximum at four days post ischemia, while the amplitude and slope of the field responses dropped to a very low level between 24 and 48 h. Disturbances of Nissl staining were finally evident at 48 h, with nearly complete disappearance of staining at five days post-ischemia. This study provides the first demonstration of a close and early temporal relationship between calpain proteolysis, subcellular damage to the pyramidal cells and their loss of function following global ischemia, prior to their eventual death.