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Neuropharmacology. 2016 Sep;108:440-50. doi: 10.1016/j.neuropharm.2015.05.014. Epub 2015 May 22.

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.

Author information

1
INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada; Laboratoire International Associé Samuel de Champlain, Université de Rouen, France; INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IRIB, Université de Rouen, 76821 Mont-Saint-Aignan, France.
2
INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada; Laboratoire International Associé Samuel de Champlain, Université de Rouen, France.
3
Laboratoire International Associé Samuel de Champlain, Université de Rouen, France; INSERM-U982, Laboratory of Neuronal and Neuroendocrine Differentiation and Communication, IRIB, Université de Rouen, 76821 Mont-Saint-Aignan, France.
4
INSERM U1149/Inflammation Research Center (CRI), Université Paris-Diderot, Faculté de Médecine Site Bichat, 16, rue H. Huchard, 75018 Paris, France.
5
INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada.
6
INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada; Laboratoire International Associé Samuel de Champlain, Université de Rouen, France. Electronic address: alain.fournier@iaf.inrs.ca.

Abstract

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), Nle(17)]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), Nle(17)]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), Nle(17)]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), Nle(17)]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.

KEYWORDS:

Dopaminergic neuron survival; Neurodegeneration; Neurodegenerative disorders; PACAP; SH-SY5Y neuroblastoma cell survival; Vasodilation

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