PACAP in Parkinson's disease: A multifunctional neuropeptide at the crossroad of autophagy, inflammation, and metabolic repurposing.
PACAP: The Neuroprotective Peptide Researchers Are Watching in Parkinson’s Disease
Neuropharmacology
by Hassan ME, Al-Kuraishy HM, Fawzy MN et al.
“PACAP in Parkinson's disease: A multifunctional neuropeptide at the crossroad of autophagy, inflammation, and metabolic repurposing. Hassan ME(1), Al-Kuraishy HM(2), Fawzy MN(3), Hussain NR(4), Al-Gareeb AI(5), Rashwan EK(6), Albuhadily AK(7), Batiha GE(8). Author information: (1)Biochemical Unit, Pathology department, Medical College, Jouf University, Sakaka, 72388, Saudi Arabia. Electronic address: metelb@ju.edu.sa. (2)Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq. Electronic address: haydermutter@uomustansiriyah.edu.iq. (3)Department of Pharmacology and Toxicology, Faculty of Pharmacy, Sinai University, Arish Branch, Arish, 45511, Egypt. Electronic address: mohamed.naser@su.edu.eg. (4)Department of Clinical Pharmacology, College of Pharmacy, Al-Farahidi University, Bagdad, Iraq. Electronic address: ph.nawar@gmail.com. (5)Jabir Ibn Hayyan Medical University, Al-Ameer Qu./Najaf PO.Box13, Kufa, Iraq. Electronic address: dr.alialgareeb78@jmu.edu.iq. (6)Department of Physiology, College of Medicine, Jouf University, Sakaka, 42421, Saudi Arabia. Electronic address: dremanrashwan2020@gmail.com. (7)Department of Clinical pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq. Electronic address: alikadhim@uomustansiriyah.edu.iq. (8)Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, AlBeheira, 22511, Egypt. Electronic address: Gaberelsaberbatiha@gmail.com. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the accumulation of α-synuclein, mitochondrial dysfunction, and chronic neuroinflammation. In this complex pathology, pituitary adenylate cyclase-activating polypeptide (PACAP) has become a crucial neuroprotective regulator; however, its signaling pathways are markedly impaired in Parkinson's disease (PD). This review consolidates the increasing evidence that PACAP counteracts the pathogenesis of PD through multiple mechanisms: restoring autophagic flux, diminishing oxidative stress, altering the balance from pro-apoptotic to anti-apoptotic pathways, and alleviating microglial-mediated neuroinflammation. Recognizing the difficulties associated with peptide-based therapies, we explore novel strategies to utilize PACAP's protective properties, including the repurposing of FDA-approved medications like linagliptin and metformin, which engage PACAP-dependent pathways. Despite preclinical models consistently demonstrating significant neuroprotective effects, there is a marked absence of clinical validation. This review integrates mechanistic insights, evidence from particular models, and potential biomarkers to establish PACAP as a promising therapeutic target and delineates a strategy for accelerating its transition from laboratory research to clinical application in PD. Copyright © 2026 Elsevier Ltd. All rights reserved. Conflict of interest statement: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.”
PACAP (pituitary adenylate cyclase-activating polypeptide) is now firmly in the Parkinson’s disease research spotlight. This neuropeptide has been called “multifunctional” for a reason. The latest review in Neuropharmacology lays out why PACAP keeps turning up in discussions about neuroprotection, autophagy, and metabolic resilience.
Here’s the short version: Parkinson’s disease is a grind of neurodegeneration, with α-synuclein buildup, mitochondrial problems, and relentless inflammation. PACAP seems to counter these breakdowns at several pressure points.
Key findings:
PACAP restores autophagic flux — basically, it helps neurons clear out cellular junk, a process that’s broken in PD.
The peptide dampens oxidative stress and tilts the balance toward cell survival, not cell death.
PACAP calms down microglial-driven inflammation, which is a big deal in progressive neurodegeneration.
Researchers are even looking at known compounds like linagliptin and metformin for their ability to activate PACAP-driven pathways.
The review points out the obvious — peptide-based therapies have their practical challenges. But the consistent results in preclinical models are hard to ignore. PACAP’s neuroprotective effects keep showing up, even if clinical trials haven’t caught up yet.
Researchers are now mapping out how to move PACAP from bench to bedside. They’re identifying biomarkers, refining delivery strategies, and cross-referencing metabolic drugs that might amplify PACAP’s benefits.
For anyone tracking the future of Parkinson’s disease research, PACAP is a name to remember. This is the kind of peptide that could change how neurodegeneration is tackled at the molecular level.
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