Neuroprotection against hypoxic-ischemic brain injury by inhibiting the apoptotic protease activating factor-1 pathway

Yanqin Gao, Weimin Liang, Xiaoming Hu, Wenting Zhang, R. Anne Stetler, Peter Vosler, Guodong Cao, Jun Chen

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE-: 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. CONCLUSION-: 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.

Original languageEnglish (US)
Pages (from-to)166-172
Number of pages7
JournalStroke
Volume41
Issue number1
DOIs
Publication statusPublished - Jan 1 2010
Externally publishedYes

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Keywords

  • Apoptosis
  • Brain ischemia
  • Neuroprotection

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

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