Temporal ordering of pathogenic events following transient global ischemia.
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.
Bartus
R T
RT
Alkermes, 64 Sidney Street, Cambridge, MA 02139, USA. rtbartus@alkermes.com
Dean
R L
RL
Mennerick
S
S
Eveleth
D
D
Lynch
G
G
D000818:Animals; D001923:Brain Chemistry / Q000502:physiology*; D002154:Calpain / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D003599:Cytoskeleton / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000201:enzymology / Q000503:physiopathology*; D002546:Ischemic Attack, Transient / Q000378:metabolism* / Q000503:physiopathology*; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016622:Silver Staining; D013049:Spectrin / Q000032:analysis; D013997:Time Factors
D013049:Spectrin; D002154:Calpain