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.