Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

• Published in: Neuropharmacology 2016-09, Vol.108, p.440-450
• Main Authors: Lamine, Asma, Létourneau, Myriam, Doan, Ngoc Duc, Maucotel, Julie, Couvineau, Alain, Vaudry, Hubert, Chatenet, David, Vaudry, David, Fournier, Alain
• Format: Article
• Language: English
• Subjects: Animals; Cardiovascular Diseases - chemically induced; Cardiovascular Diseases - prevention & control; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - physiology; CHO Cells; Cricetinae; Cricetulus; Dopaminergic neuron survival; Dose-Response Relationship, Drug; Humans; Life Sciences; Male; Mice; Mice, Inbred C57BL; Neurodegeneration; Neurodegenerative disorders; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; PACAP; Parkinsonian Disorders - drug therapy; Parkinsonian Disorders - metabolism; Pituitary Adenylate Cyclase-Activating Polypeptide - chemistry; Pituitary Adenylate Cyclase-Activating Polypeptide - pharmacology; Pituitary Adenylate Cyclase-Activating Polypeptide - therapeutic use; SH-SY5Y neuroblastoma cell survival; Vasodilation
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2015.05.014

Parkinson's disease (PD) is characterized by a steady loss of dopamine neurons through apoptotic, inflammatory and oxidative stress processes. In that line of view, the pituitary adenylate cyclase-activating polypeptide (PACAP), with its ability to cross the blood–brain barrier and its anti-apoptotic, anti-inflammatory and anti-oxidative properties, has proven to offer potent neuroprotection in various PD models. Nonetheless, its peripheral actions, paired with low metabolic stability, hampered its clinical use. We have developed Ac-[Phe(pI)6, Nle17]PACAP(1-27) as an improved PACAP-derived neuroprotective compound. In vitro, this analog stimulated cAMP production, maintained mitochondrial potential and protected SH-SY5Y neuroblastoma cells from 1-methyl-4-phenylpyridinium (MPP+) toxicity, as potently as PACAP. Furthermore, contrasting with PACAP, it is stable in human plasma and against dipeptidyl peptidase IV activity. When injected intravenously to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice, PACAP and Ac-[Phe(pI)6, Nle17]PACAP(1-27) restored tyrosine hydoxylase expression into the substantia nigra and modulated the inflammatory response. Albeit falls of mean arterial pressure (MAP) were observed with both PACAP- and Ac-[Phe(pI)6, Nle17]PACAP(1-27)-treated mice, the intensity of the decrease as well as its duration were significantly less marked after iv injections of the analog than after those of the native polypeptide. Moreover, no significant changes in heart rate were measured with the animals for both compounds. Thus, Ac-[Phe(pI)6, Nle17]PACAP(1-27) appears as a promising lead molecule for the development of PACAP-derived drugs potentially useful for the treatment of PD or other neurodegenerative diseases. [Display omitted] •Ac-[Phe(pI)6, Nle17]PACAP(1-27) is an analog that is metabolically stable.•The analog protects in vitro SH-SY5Y neuroblastoma cells from MPP+ toxicity.•The analog protects substantia nigra dopaminergic neurons from MPTP toxicity.•Ac-[Phe(pI)6, Nle17]PACAP(1-27) decreases apoptotic and inflammatory responses.•Ac-[Phe(pI)6, Nle17]PACAP(1-27) is a weaker vasodilator than PACAP.