Journal
CURRENT PHARMACEUTICAL DESIGN
Volume 17, Issue 3, Pages 204-214Publisher
BENTHAM SCIENCE PUBL LTD
DOI: 10.2174/138161211795049679
Keywords
Apoptosis; Bcl-2; caspase; neuroprotection; PACAP; PAC1
Categories
Funding
- INSERM [U982]
- European Institute for Peptide Research [IFRMP23]
- IREB
- Interreg IVA
- Conseil Regional de Haute-Normandie
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Apoptosis is a regulated process leading to cell death, which is implicated both in normal development and in various pathologies including heart failure, stroke and neurodegenerative diseases. Caspase-3, a key enzyme of the apoptotic pathway, is considered as a major target for the treatment of abnormal cell death. Many factors that inhibit cell death have been identified, but the mechanisms involved are not always fully understood. Pituitary adenylate cylase-activating polypeptide (PACAP) has been shown to exert neuroprotective activities during development. PACAP also inhibits apoptosis in cardiomyopathy, decreases glutamate-induced retinal injury, reduces neuronal loss in case of stroke, and prevents ethanol neurotoxicity. Most of the antiapoptotic effects of PACAP are mediated through the PAC1 receptor. This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression which inhibits cytochrome c release and blocks in turn caspase activation. PACAP also acts through the PI3K/Akt pathway and inhibits the expression of proapoptotic factors such as c-Jun or Bax. The remarkable effect of PACAP on the apoptotic cascade suggests that innovative PACAP derivatives could potentially be useful for treatment of post-traumatic lesions, chronic neurodegenerative diseases, cardiac ischemia and/or retinopathy.
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