PTD-XIAP protects against cerebral ischemia by anti-apoptotic and transcriptional regulatory mechanisms.
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.
Guégan
Christelle
C
INSERM UMR421, Universite Paris 12, 8, rue du Général Sarrail, F-94010 Creteil cedex, France.
Braudeau
Jérôme
J
Couriaud
Cécile
C
Dietz
Gunnar P H
GP
Lacombe
Pierre
P
Bähr
Mathias
M
Nosten-Bertrand
Marika
M
Onténiente
Brigitte
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002545:Brain Ischemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D004195:Disease Models, Animal; D015696:Gene Products, tat / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D007260:Infusion Pumps; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D050436:Regulatory Elements, Transcriptional / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
D015696:Gene Products, tat; D011993:Recombinant Fusion Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein