BDNF blocks caspase-3 activation in neonatal hypoxia-ischemia.
Hypoxic-ischemic (H-I) injury to the brain in the perinatal period often leads to significant long-term neurological deficits. In a model of neonatal H-I injury in postnatal day 7 rats, our previous data have shown that cell death with features of apoptosis is prominent between 6 and 24 h after H-I and that neurotrophins, particularly BDNF, can markedly protect against tissue loss. During brain development, caspase-3 is required for normal levels of programmed cell death. Utilizing an antibody specific for the activated form of caspase-3, CM1, we now show that caspase-3 is specifically activated in neuronal cell bodies and their processes beginning at 6 h and peaking 24 h following unilateral carotid ligation and exposure to hypoxia in postnatal day 7 rats. Caspase-3 activation began to occur in cortex at 6 h and in striatum and hippocampus at 12-18 h. Caspase-3 activation was also observed in developing oligodendrocytes. Intracerebroventricular injection of BDNF prior to H-I injury almost completely abolished evidence of H-I-induced caspase-3 activation in vivo. Utilizing a specific molecular marker of an apoptotic pathway, these findings demonstrate that H-I injury to the developing brain is a strong apoptotic stimulus leading to caspase-3 activation, that BDNF can block this process in vivo, and that the ability of BDNF to inhibit caspase activation and subsequent apoptosis likely accounts in large part for its protection against neuronal injury in this model.
Han
B H
BH
Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
D'Costa
A
A
Back
S A
SA
Parsadanian
M
M
Patel
S
S
Shah
A R
AR
Gidday
J M
JM
Srinivasan
A
A
Deshmukh
M
M
Holtzman
D M
DM
D000818:Animals; D000831:Animals, Newborn; D000918:Antibody Specificity; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D007839:Functional Laterality; D002534:Hypoxia, Brain / Q000201:enzymology* / Q000473:pathology; D009474:Neurons / Q000473:pathology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley
D019208:Brain-Derived Neurotrophic Factor; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases