TEMPORAL ORDERING OF PATHOGENIC EVENTS FOLLOWING TRANSIENT GLOBAL-ISCHEMIA

Rats were subjected to transient global ischemia (four vessel occlusio n) and time-related changes in the selectively vulnerable hippocampal field CA1 were characterized. The assessment included ex vivo field re sponses to afferent stimulation, silver staining, calpain-induced spec trin breakdown, chromatolysis, and cell death, beginning at 6 h post-i schemia and continuing until total disintegration of the pyramidal cel ls occurred several days later. The earliest change observed was a mod est increase in the slope and amplitude of field CAI potentials (at 6 h). The hyperresponsiveness was most apparent at higher stimulation cu rrents and persisted unchanged at 16 h post-ischemia. Three effects be came detectable within 24 h, post-ischemia: (a) an increase in concent rations of calpain-mediated, spectrin breakdown products; (b) enhanced silver staining in the deep pyramidal neurons of the field CA1 with l esser, though still apparent, staining of stratum radiatum, and (c) a decrease in amplitude and slope of field CA1 responses to afferent sti mulation. Both the concentration of spectrin breakdown products and th e intensity of silver staining progressively increased to a maximum at four days post ischemia, while the amplitude and slope of the field r esponses 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 provi des the first demonstration of a close and early temporal relationship between calpain proteolysis, subcellular damage to the pyramidal cell s and their loss of function following global ischemia, prior to their eventual death. (C) 1998 Elsevier Science B.V.