Neuroprotection against hypoxic-ischemic brain injury by inhibiting the apoptotic protease activating factor-1 pathway.
OBJECTIVE
Emerging evidence suggests that mitochondrial damage-mediated neuronal apoptosis is a major contributor to neonatal hypoxic-ischemic (H-I) brain injury. This study was performed to determine whether targeted inhibition of the apoptotic protease activating factor-1 (Apaf-1) signaling pathway downstream of mitochondrial damage confers neuroprotection in rodent models of neonatal H-I.


METHODS
H-I was induced in 7-day-old (P7) transgenic mice overexpressing the specific Apaf-1-inhibitory protein AIP. Apaf-1 inhibition was also achieved in P7 rats by protein transduction-enhanced delivery of recombinant AIP. Pups were euthanized 6 to 24 hours after H-I for assessing caspase activation and mitochondrial release of cytochrome c and AIF, and 7 days after H-I for analyzing brain tissue damage. Sensorimotor functions were assessed in rats up to 4 weeks after H-I.


RESULTS
Transgenic overexpression of AIP protected against H-I brain injury, resulting in attenuated activation of caspase-9 and caspase-3, and attenuated brain tissue loss. In neonatal H-I rats, intraperitoneal injection of TAT-AIP, but not the control proteins TAT-GFP or AIP, decreased caspase activation and brain damage and improved neurological functions. Neuroprotection conferred by AIP was also associated with significantly reduced release of cytochrome c and AIF from mitochondria.


CONCLUSIONS
The Apaf-1 signaling pathway, which transmits cell death signals after mitochondrial damage to effector caspases, may be a legitimate therapeutic target for the treatment of neonatal H-I brain injury.
Gao
Yanqin
Y
State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, China. yanqin.gao@gmail.com
Liang
Weimin
W
Hu
Xiaoming
X
Zhang
Wenting
W
Stetler
R Anne
RA
Vosler
Peter
P
Cao
Guodong
G
Chen
Jun
J
D000818:Animals; D000831:Animals, Newborn; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D004195:Disease Models, Animal; D020925:Hypoxia-Ischemia, Brain / Q000201:enzymology / Q000378:metabolism / Q000517:prevention & control*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051381:Rats; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
D053477:Apoptotic Protease-Activating Factor 1; D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein