Abstract
Caspases play a major role in the infarction process that follows occlusion of cerebral arteries and are important targets for stroke therapy. We have generated three fusion proteins that link various domains of the X chromosome-linked inhibitor of apoptosis (XIAP), a potent caspase inhibitor, to the protein transduction domain (PTD) of HIV-1/Tat, and have tested their efficacy after distal occlusion of the middle cerebral artery (dMCAO) in mice. PTD-XIAP failed to accumulate in brain structures after intravenous (iv) delivery, but properly transduced cortical cells when applied topically. Shorter constructs efficiently targeted the lesion after iv delivery. All proteins retained their caspase inhibitory activity and significantly reduced infarct volumes. PTD-XIAP reversed long-term impairments in the water maze test. Sequential activation of transcription factors was observed, suggesting that the effects of XIAP are mediated by both direct inhibition of apoptotic mechanisms and secondary regulation of transcription factors involved in neuronal survival.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Apoptosis / genetics
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Brain Ischemia / drug therapy*
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Brain Ischemia / genetics
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Brain Ischemia / metabolism
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Cerebral Cortex / drug effects*
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Cerebral Cortex / metabolism
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Cerebral Cortex / physiopathology
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Cerebral Infarction / drug therapy
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Cerebral Infarction / physiopathology
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Cerebral Infarction / prevention & control
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Disease Models, Animal
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Gene Products, tat / genetics
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Gene Products, tat / pharmacology
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Gene Products, tat / therapeutic use
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Infarction, Middle Cerebral Artery / drug therapy
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Infarction, Middle Cerebral Artery / genetics
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Infarction, Middle Cerebral Artery / metabolism
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Infusion Pumps
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Male
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Maze Learning / drug effects
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Maze Learning / physiology
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Mice
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Mice, Inbred C57BL
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Protein Structure, Tertiary / genetics
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / pharmacology*
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Recombinant Fusion Proteins / therapeutic use
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Regulatory Elements, Transcriptional / drug effects
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Regulatory Elements, Transcriptional / genetics
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology
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X-Linked Inhibitor of Apoptosis Protein / genetics
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X-Linked Inhibitor of Apoptosis Protein / pharmacology*
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X-Linked Inhibitor of Apoptosis Protein / therapeutic use
Substances
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Gene Products, tat
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Recombinant Fusion Proteins
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X-Linked Inhibitor of Apoptosis Protein