CREB activation in the rapid, intermediate, and delayed ischemic preconditioning against hypoxic-ischemia in neonatal rat.
Ischemic preconditioning (IP) is a defense program in which exposure to sublethal ischemia followed by a period of reperfusion results in subsequent resistance to severe ischemic insults. Very few in vivo IP models have been established for neonatal brain. We examined whether rapid, intermediate, and delayed IP against hypoxic-ischemia (HI) could be induced in neonatal brain, and if so, whether the IP involved phosphorylation of cAMP response element-binding protein (pCREB) after HI. Postnatal day 7 rat pups were subjected to HI at 2 h (2-h IP), 6 h (6-h IP), or 22 h (22-h IP) after IP. We found all three IP groups had significantly reduced neuronal damage and TUNEL-(+) cells 24 h post-HI than no-IP group. Compared with control, the no-IP group had significant decreases of pCREB and mitochondria Bcl-2 levels in the ipsilateral cortex 24 h post-HI. In contrast, the three IP groups had increased pCREB and mitochondria Bcl-2 levels, and significant differences were found between three IP and no-IP groups. The increases of cleavage of caspase-3 and poly (ADP-ribose) polymerase and of cells with nuclear apoptosis inducing factor post-HI in no-IP group were all significantly reduced in three IP groups. The increases of caspase-3 and calpain-mediated proteolysis of a-spectrin post-HI were significantly reduced only in 22-h IP group. Furthermore, all three IP groups had long-term neuroprotection at behavioral and pathological levels compared with no-IP group. In conclusion, IP, rapid, intermediate, or delayed, in neonatal rat brain activates CREB, up-regulates Bcl-2, induces extensive brakes on caspase-dependent and -independent apoptosis after HI, and provides long-term neuroprotection.
Lin
Wan-Ying
WY
Institute of Basic Medical Sciences, National Cheng Kung University Medical College, Tainan, Taiwan.
Chang
Ying-Chao
YC
Lee
Hsueh-Te
HT
Huang
Chao-Ching
CC
D000375:Aging / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D001921:Brain / Q000254:growth & development / Q000378:metabolism* / Q000503:physiopathology; D020520:Brain Infarction / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053148:Caspase 3 / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D019610:Cytoprotection / Q000502:physiology; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3