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Pituitary adenylate cyclase activating polypeptide (PACAP) is an ubiquitous peptide involved, among others, in neurodevelopment, neuromodulation, neuroprotection, neurogenic inflammation and nociception. Presence of PACAP and its specific receptor, PAC1, in the trigeminocervical complex, changes of PACAP levels in migraine patients and the migraine-inducing effect of PACAP injection strongly support the involvement of PACAP/PAC1 receptor in migraine pathogenesis. While antagonizing PAC1 receptor is a promising therapeutic target in migraine, the diverse array of PACAP’s functions, including protection in ischemic events, requires that the cost-benefit of such an intervention is well investigated by taking all the beneficial effects of PACAP into account. In the present review we summarize the protective effects of PACAP in ischemia, especially in neuronal ischemic injuries, and discuss possible points to consider when developing strategies in migraine therapy interfering with the PACAP/PAC1 receptor system.

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Citation: Werling D, Reglodi D, Banks WA, et al. Ocular delivery of PACAP1-27 protects the retina from ischemic damage in rodents. Invest Ophthalmol Vis Sci. 2016;57:6683-6691. DOI: 10.1167/iovs.16-20630 PURPOSE. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in neuronal injuries. Bilateral common carotid artery occlusion (BCCAO) causes chronic hypoperfusion-induced degeneration in the rat retina, where we proved the retinoprotective effect of intravitreal PACAP. Although this route of administration is a common clinical practice in several diseases, easier routes are clinically important. Our aim was to investigate the potential retinoprotective effects of PACAP eye drops in BCCAO-induced ischemic retinopathy.METHODS. After performing BCCAO in rats, the right eyes were treated with PACAP1-27 eye drops (1 lg/drop, 2 3 1 drops/day for 5 days), containing different vehicles: saline, water for injections, thiomersal or benzalkonium solution for ophthalmic use (SOCB). Histology and immunohistochemistry were performed 2 weeks after surgery, while molecular analysis was performed 24 hours after BCCAO. Passage of PACAP1-27 through the ocular layers was tested with radioactive PACAP-SOCB in mice.RESULTS. Bilateral common carotid artery occlusion led to a severe degeneration of all retinal layers. Solution for ophthalmic use was the most effective vehicle for delivering PACAP (PACAP-SOCB), significantly ameliorating BCCAO-induced damage. The massive upregulation of GFAP was not observed in retinas treated with PACAP-SOCB eye drops. PACAP-SOCB treatment also increased activation of the protective Akt and ERK1/2 in hypoperfused retinas. The cytokine profile showing upregulation in different cytokines was attenuated by PACAP-SOCB. Radioactive PACAP reached the retina when delivered in SOCB-containing eye drops.CONCLUSIONS. PACAP1-27, delivered in the SOCB vehicle as eye drops, was retinoprotective in ischemic retinopathy, providing the basis for future therapeutic administration.

Objective: Pituitary adenylate cyclase activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide widely distributed throughout the body. It is involved in the regulation of various physiological and pathophysiological processes, such as reproduction, thermoregulation, motor activity, brain development, neuronal survival, inflammation and pain. Since little is known about its distribution in humans, our aim was to examine PACAP-38 in human plasma. Furthermore, based on the presence of vasoactive intestinal peptide, structurally the closest to PACAP, in milk and PACAP and its receptors in the mammary gland, our aim was to study PACAP-38 in human milk. Design and methods: The presence of PACAP-38 was determined by mass spectrometry in plasma samples from healthy male and female volunteers (age: 20-40), as well as in plasma and milk samples from lactating women (age: 20-35). PACAP concentration was measured with a specific and sensitive RIA. Results: Our results revealed that PACAP-38 is present in human plasma, its concentration is relatively stable in healthy volunteers and it is not significantly altered by gender, age, food intake or hormonal cycle in females. However, PACAP-38 plasma levels significantly increased in lactating women having 1-6 month-old babies. Moreover, this study is the first which provides evidence for the presence of PACAP-38 in the human milk with levels 5-20-fold greater in the milk whey than in the respective plasma samples. Conclusions: We found PACAP-38 in human plasma and its increase during the first 6 months of the lactation period. A prominent, nearly 10-fold higher concentration of this peptide was detected in human milk. Based on the literature, several important actions of milk-derived PACAP-38 can be suggested such as mammary gland proliferation, nutrient transfer as well as regulation of growth/differentiation of certain tissues of the neonates. The novelty of the present descriptive data provides a basis for further investigations on the mechanism of PACAP-38 secretion in human milk and its functional significance.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a widespread neuropeptide that is well known for its general cytoprotective effects in different neuronal injuries, such as traumatic brain and spinal cord injury, models of neurodegenerative diseases, and cerebral ischemia. PACAP and its receptors also occur in the retina. In this review, we summarize the retinoprotective effects of PACAP. In vitro, PACAP is protective against glutamate, thapsigargin, anisomycin, oxidative stress, UV light, high glucose, infl ammation, and anoxia. Both the neural retina and the pigment epithelial cells can be protected by PACAP in various experimental paradigms. In vivo, the protective effects of intravitreal PACAP treatment have been shown in the following models in rats and mice: excitotoxic injury induced by glutamate, N -methyl-D -aspartate (NMDA) or kainate, ischemic injury induced by carotid artery ligation and high intraocular pressure, degeneration caused by UV-A light, optic nerve transection, and streptozotocin-induced diabetic retinopathy as well as retinopathy of prematurity. Molecular biological methods have revealed that PACAP activates anti-apoptotic, while inhibits pro-apoptotic signaling pathways, and it also stimulates an anti-infl ammatory environment in the retina. Altogether, PACAP is suggested to be a potential therapeutic retinoprotective agent in various retinal diseases.

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Purpose. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroprotective peptide that has been shown to exert protective effects in different models of neurodegenerative diseases, including retinal degenerations. Data obtained from PACAPdeficient (PACAP KO) mice provide evidence that endogenous PACAP has neuroprotective role in different pathologies. PACAP KO mice show enhanced sensitivity to different insults, such as oxidative stress, hypoxia and inflammation. The aim of the present study was to investigate the protective effects of endogenous PACAP in retinal inflammation. Methods. Endotoxin-caused eye inflammation was induced by intraperitoneal injection of lipopolysaccharide (LPS) in PACAP KO and wild type (Wt) mice. After LPS treatment, retinas were processed for histological examination. To detect the alterations of different proteins and cytokines, immunohistochemical, western blot and cytokine array were used. We also performed dark-adapted electroretinography (ERG) to detect the functional differences. Results. The thickness of nearly all layers was significantly less in LPS-injected PACAP KO mice compared to Wt animals. Increased expression of glial fibrillary acidic protein (GFAP) was induced in Müller glial cells after LPS treatment, which was more intense in PACAP KO mice. The levels of pAkt and pGSK were decreased in PACAP KO group during inflammation. LPS treatment significantly increased cytokines (sICAM-1, JE, TIMP-1) in both treated groups, but it was more expressed in PACAP KO animals. Furthermore, ERG responses were disturbed after LPS injection in PACAP KO mice. Conclusion. Our results showed that endogenous PACAP has a protective role in LPS-caused retinal inflammation.