PACAP-38
preclinicalAlso known as: Pituitary adenylate cyclase-activating polypeptide
PACAP-38 (pituitary adenylate cyclase-activating polypeptide) is a 38-amino acid neuropeptide belonging to the vasoactive intestinal peptide (VIP)/secretin family. Its primary mechanism of action involves high-affinity binding to the PAC1 receptor, a G protein-coupled receptor that activates adenylate cyclase, leading to increased cyclic AMP (cAMP) levels. This signaling cascade mediates neuroprotective effects, including inhibition of apoptosis, modulation of neuroinflammation, and promotion of neuronal survival. Additionally, PACAP-38 exerts vasoregulatory functions by inducing vasodilation in cerebral and peripheral vasculature, partly through nitric oxide-dependent pathways. Preclinical research (over 3,100 PubMed-indexed studies) has demonstrated PACAP-38's efficacy in models of ischemic stroke, traumatic brain injury, and neurodegenerative diseases such as Parkinson's and Alzheimer's. It reduces infarct volume, attenuates oxidative stress, and supports blood-brain barrier integrity. In migraine models, PACAP-38 infusion triggers headache-like responses, implicating PAC1 receptors in migraine pathophysiology. Studies also highlight its role in stress adaptation, circadian rhythm regulation, and neuroendocrine modulation. Despite robust preclinical evidence, PACAP-38 remains in the preclinical stage, with no approved clinical applications. Its therapeutic potential is limited by rapid enzymatic degradation and poor blood-brain barrier penetration. Ongoing research focuses on developing stable analogs, receptor-selective agonists, and delivery systems to translate these neuroprotective and vasoregulatory properties into viable treatments for neurological and vascular disorders. For research purposes only — not medical advice.
Key data
C203H331N63O53SResearch & studies
PACAP infusions can provoke migraine attacks in patients.; A monoclonal antibody against the PACAP-receptor failed in a placebo-controlled study.; Lu AG09222 reduced monthly migraine days versus placebo but did not meet the 50% reduction endpoint.; The PROCEED study, testing four doses of Lu AG09222, is expected to complete in 2025.
PACAP is a key neurotransmitter in the adrenal medulla that provokes strong secretory responses from chromaffin cells.; The cellular mechanisms underlying PACAP-stimulated secretion remain poorly understood.; PACAP acts alongside acetylcholine to regulate hormone release, including epinephrine and norepinephrine.
PACAP-deficient mice show longer AIS length in layer 2/3 pyramidal neurons of the primary somatosensory barrel field.; Repeated atomoxetine treatment improved AIS abnormality and hyperactivity in PACAP-deficient mice.; AIS abnormalities are associated with neurodevelopmental disorder-like behaviors in PACAP-deficient mice.
PACAP regulates neuronal physiology and transcription via Gs/Gq-coupled receptors, influencing stress, affect, neuroprotection, and cognition.; Elevated PACAP levels and PAC1 receptor disruptions in humans are associated with maladaptive threat learning and PTSD.; PACAP integrates stress and memory, but its role in memory processes is less studied than its role in stress.; Emerging data suggest sex differences in PACAP signaling relevant to fear learning.
PACAP is a cytoprotective neuropeptide involved in neuronal proliferation, differentiation, migration, and neuroprotection.; PACAP shows potential as a treatment for stroke by targeting mechanisms like ionic homeostasis, excitotoxicity, cell edema, oxidative stress, inflammation, and cell death.; The review discusses various routes of PACAP administration for stroke therapy.
PACAP and its receptors are expressed during chondrogenesis and activate pathways regulating cartilage development.; PACAP is chondroprotective against oxidative stress, hypoxia, inflammation, and apoptosis that cause cartilage degeneration.; Degenerated cartilage in osteoarthritis exhibits low levels of PACAP, indicating its role in maintaining physiological properties.; Exogenous PACAP administration could be a potential tool to slow OA progression and aid cartilage regeneration.
PACAP improves stroke outcomes and dementia in animal models.; PACAP can cross the blood-brain barrier, aiding in therapy for neurodegenerative diseases.; PACAP may function as a potential drug for treatment, prevention, or management of stroke and Alzheimer's disease.
Frequently asked questions
What is PACAP-38?
PACAP-38 (pituitary adenylate cyclase-activating polypeptide) is a 38-amino acid neuropeptide belonging to the vasoactive intestinal peptide (VIP)/secretin family. Its primary mechanism of action involves high-affinity binding to the PAC1 receptor, a G protein-coupled receptor that activates adenylate cyclase, leading
How does PACAP-38 work?
38-aa neuropeptide of the VIP/secretin family acting on PAC1 receptors; neuroprotective and vasoregulatory.
What is the research status of PACAP-38?
PACAP-38 is currently classified as preclinical, with 3,114 research references on record. This is for research purposes only and is not medical advice.
What is the molecular weight of PACAP-38?
PACAP-38 has a molecular weight of approximately 4534 g/mol (formula C203H331N63O53S).
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