Attenuation of ischemia-induced cellular and behavioral deficits by X chromosome-linked inhibitor of apoptosis protein overexpression in the rat hippocampus.
Transient forebrain ischemia produced by four-vessel occlusion (4-VO) triggers the delayed death of CA1 neurons in the hippocampus, resulting in behavioral deficits of spatial learning performance. We demonstrate that CA1 neuronal loss induced by 4-VO (12 min) is preceded by a selective and marked elevation of catalytically active caspase-3 in these neurons, indicative of apoptosis. Virally mediated overexpression of the anti-apoptotic gene X chromosome-linked inhibitor of apoptosis protein (XIAP) prevented both the production of catalytically active caspase-3 and degeneration of CA1 neurons after transient forebrain ischemia. CA1 neurons protected in this manner appeared to function normally, as assessed by immunohistochemical detection of the neuronal activity marker nerve growth factor inducible-A and by spatial learning performance in the Morris water maze. These findings indicate that caspase-3 activation is a key event in ischemic neuronal death and that blockade of this event by XIAP overexpression permits CA1 neurons to survive and operate properly after an ischemic insult.
Xu
D
D
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario K1H 8M5, Canada.
Bureau
Y
Y
McIntyre
D C
DC
Nicholson
D W
DW
Liston
P
P
Zhu
Y
Y
Fong
W G
WG
Crocker
S J
SJ
Korneluk
R G
RG
Robertson
G S
GS
D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D001522:Behavior, Animal / Q000502:physiology; D001923:Brain Chemistry / Q000235:genetics; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006624:Hippocampus / Q000098:blood supply / Q000737:chemistry / Q000166:cytology*; D002546:Ischemic Attack, Transient / Q000503:physiopathology*; D008297:Male; D018782:Maze Learning / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D051616:Neuronal Apoptosis-Inhibitory Protein; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000201:enzymology; D011506:Proteins / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D014960:X Chromosome; D051636:X-Linked Inhibitor of Apoptosis Protein
C496803:Naip6 protein, rat; D009419:Nerve Tissue Proteins; D051616:Neuronal Apoptosis-Inhibitory Protein; D011506:Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases