Pituitary adenylate cyclase-activating polypeptide, or PACAP, is a signaling molecule found throughout the body. This neuropeptide belongs to a family of peptides that includes vasoactive intestinal peptide (VIP) and secretin. PACAP exerts widespread influence, participating in a broad range of biological processes.
The Role and Location of PACAP in the Body
PACAP is closely related to vasoactive intestinal peptide (VIP). It exists in two main forms, PACAP-38 and PACAP-27, with PACAP-38 being the more prevalent form in mammals. PACAP is broadly distributed across various bodily systems, including the central nervous system (brain and spinal cord).
Beyond the central nervous system, PACAP is also found in peripheral organs such as the adrenal glands, pancreas, gut, and reproductive organs. Its effects are mediated through three main receptors: PAC1, VPAC1, and VPAC2. The PAC1 receptor specifically binds PACAP with high affinity, while VPAC1 and VPAC2 receptors show similar affinity for both PACAP and VIP. The specific receptor type present in a particular tissue or cell dictates the resulting physiological response to PACAP.
PACAP’s Influence on the Nervous System
PACAP plays a role in the body’s response to stress. It activates the hypothalamic-pituitary-adrenal (HPA) axis, which regulates reactions to various stressors. PACAP is necessary for the sustained function of this axis, influencing the release of corticotropin-releasing hormone (CRH) from the hypothalamus and subsequent hormone secretions. Deficiencies in PACAP can significantly diminish major portions of both central and peripheral stress responses.
PACAP also exhibits neuroprotective properties, protecting neurons from damage. It helps prevent neuronal apoptosis, a form of programmed cell death, in various models of brain injuries such as cerebral ischemia and Parkinson’s disease. This protective action can occur directly on neurons or indirectly by stimulating the release of neuroprotective factors from supporting cells like astrocytes. The peptide also contributes to neurodevelopment by guiding the growth and survival of brain cells, with its expression being particularly high in the embryonic brain during neurogenesis.
Connection to Pain and Migraines
PACAP is involved in the transmission and sensitization of pain signals. Studies in rodents show that PACAP administration can sensitize neurons to pain, while blocking PACAP activity can reduce pain sensitivity. This neuropeptide is expressed throughout the trigeminovascular system, a network of nerves and blood vessels in the head relevant to headache disorders.
Research focuses on PACAP’s connection to migraines. Elevated levels of PACAP-38 have been detected in the blood plasma of individuals during spontaneous migraine attacks. Infusing PACAP-38 intravenously can trigger migraine-like headaches in individuals susceptible to migraines, with attacks typically developing within two to three hours after infusion. This highlights PACAP as a mediator in migraine pathophysiology.
Impact on Metabolism and Systemic Health
PACAP also influences metabolic processes and systemic health. It is found in the pancreas, where it plays a role in regulating the secretion of insulin and glucagon. PACAP stimulates the release of both hormones, which are important for balanced blood sugar levels. This neuropeptide is localized to pancreatic nerves and within the secretory granules of insulin and glucagon cells themselves.
PACAP also contributes to energy balance. It can decrease food intake and increase metabolic rate, primarily through actions in the hypothalamus. PACAP is involved in thermoregulation, the process of maintaining body temperature. Studies suggest it influences both heat production and dissipation, and its absence can lead to impaired thermoregulatory responses.
Therapeutic and Research Frontiers
Understanding PACAP’s roles has opened new avenues for therapeutic development. Research involves targeting PACAP or its receptors for migraine prevention and treatment. Scientists are developing drugs that can block the PAC1 receptor or monoclonal antibodies designed to neutralize PACAP itself. One such monoclonal antibody, Lu AG09222, demonstrated a statistically significant reduction in monthly migraine days in a phase 2 clinical trial.
Beyond migraines, PACAP is being investigated as a potential therapeutic target for other conditions. Its neuroprotective properties make it a candidate for treating neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. PACAP administration has shown promise in animal models by inhibiting pathological processes and alleviating symptoms in these conditions. Research also explores its role in stress-related psychiatric disorders such as post-traumatic stress disorder (PTSD), where altered PACAP levels and receptor signaling have been observed in affected individuals.