title: 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.
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.
authors.affiliation: 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.
authors.forename: Asma
authors.initials: A
authors.lastname: Lamine
authors.affiliation: INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada; Laboratoire International Associé Samuel de Champlain, Université de Rouen, France.
authors.forename: Myriam
authors.initials: M
authors.lastname: Létourneau
authors.affiliation: INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada; Laboratoire International Associé Samuel de Champlain, Université de Rouen, France.
authors.forename: Ngoc Duc
authors.initials: ND
authors.lastname: Doan
authors.affiliation: 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.
authors.forename: Julie
authors.initials: J
authors.lastname: Maucotel
authors.affiliation: INSERM U1149/Inflammation Research Center (CRI), Université Paris-Diderot, Faculté de Médecine Site Bichat, 16, rue H. Huchard, 75018 Paris, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Couvineau
authors.affiliation: 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.
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.affiliation: INRS - Institut Armand-Frappier, 531 boul. des Prairies, Laval, QC H7V 1B7, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Chatenet
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.affiliation: 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.
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
mesh_terms: D000818:Animals; D016466:CHO Cells; D002318:Cardiovascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C495401:ADCYAP1 protein, human; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide
keywords: Dopaminergic neuron survival; Neurodegeneration; Neurodegenerative disorders; PACAP; SH-SY5Y neuroblastoma cell survival; Vasodilation