How to improve PACAP efficiency for neuroprotection and neurorepair?

• Published in: Neuropeptides (Edinburgh) Vol. 65; p. 142
• Main Authors: Vaudry, David, Brifault, Coralie, Letourneau, Myriam, Vaudry, Hubert, Chatenet, David, Wurtz, Olivier, Fournier, Alain
• Format: Journal Article
• Language: English
• Published: London Elsevier Ltd 01.10.2017; Elsevier Science Ltd
• Subjects: Blood pressure; Brain; Dopamine receptors; Food intake; Inflammation; Movement disorders; Neurodegenerative diseases; Neuropeptides; Neuroprotection; PAC1 protein; Parkinson's disease; Pituitary adenylate cyclase-activating polypeptide; Proteins; Recovery of function; Side effects; Stem cells
• ISSN: 0143-4179; 1532-2785
• DOI: 10.1016/j.npep.2017.02.047

PACAP and its receptors are widely expressed in the brain and peripheral organs where they exert many biological functions. Nevertheless, it is assumed that the use of PACAP as a clinically efficient drug is limited by its poor metabolic stability. Thus stable PACAP analogs such as acetyl-[Ala15, Ala20]PACAP38-propylamide have been developed, which were more potent than PACAP to inhibit food intake but did not enhanced its neuroprotective effect. PACAP acts on 3 different receptors and when injected i.v., it can induce through PAC1 and VPAC2 cardiovascular side effects. Thus, we developed Ac-[Phe(pI)6, Nle17]PACAP(l-27), a PAC1/VPAC1 agonist, which in spite of its higher metabolic stability, produced lower effects than PACAP38 on mean arterial blood pressure when given intravenously at doses shown to protect efficiently dopaminergic neurons in a model of Parkinson's disease. Another possibility to avoid PACAP side effects is to deliver the peptide locally toward the lesion area as was done with stem cells producing PACAP. Such experiments revealed that delivery of PACAP in the vicinity of the infarct zone 3 days post stroke promotes fast, stable, and efficient functional recovery. Such effect was correlated with a modulation of the postischemic inflammatory response.