The PACAP-derived peptide MPAPO facilitates corneal wound healing by promoting corneal epithelial cell proliferation and trigeminal ganglion cell axon regeneration

Wang, Zixian; Shan, Wailan; Li, Huixian; Feng, Jia; Lu, Shiyin; Ou, Biqian; Ma, Min; Ma, Yi

doi:10.7150/ijbs.35630

Cited by 19 publications

(11 citation statements)

References 54 publications

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“…In addition to the inner and middle layers of the eye, we found strong immunoreactivity in the cornea part of the outermost, brous layer of the eye, where the outer epithelial and inner endothelial layers were positive for both the peptide and its receptor. PACAP treatment on the corneal surface has been shown to induce recovery of the epithelial cells and also of the sensory innervation (Fukiage et al 2007;Ma et al 2015;Wang et al 2019). PACAP KO mice present dry eye symptoms with corneal hyperkeratinization, also pointing at the importance of endogenous PACAP (Nakamachi et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

Patko

Szabó

Tóth

et al. 2022

Preprint

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Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide with widespread distribution and diverse biological functions. Several studies show that PACAP has strong cytoprotective effects mediated mostly through its specific PAC1 receptor (PAC1-R) and it plays important roles in several pathological conditions. Its distribution and altered expression are known in various human tissues, but there is no descriptive data about PACAP and its receptors in the human eyebulb. Since the PACAP38 is the dominant form of the naturally occurring PACAP, our aim was to investigate the distribution of PACAP38-like immunoreactivity in the human eye and to describe the presence of PAC1-R. Semiquantitative evaluation was performed after routine histology and immunohistochemical labeling on human eye sections. Our results showed high level of immunopositivity in the corneal epithelium and endothelium. Within the vascular layer the iris and the ciliary body had strong immunopositivity for both PACAP and the PAC1-R. Several layers of the retina showed immunoreactivity for PACAP and PAC1-R, but the ganglion cell layer had a special pattern in the immunolabeling. Labeling was observed in the neuropil within the optic nerve in both cases and glial cells displayed immunoreactivity for PAC1-R. In summary, our study indicates the widespread occurrence of PACAP and its specific receptor in the human eye, implying that the results from in vitro and animal studies have translational value and most probably are also present in the human eye.

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Section: Discussionmentioning

confidence: 99%

Distribution of PACAP and PAC1 Receptor in the Human Eye

Patko

Szabó

Tóth

et al. 2022

Preprint

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“…Indeed, PACAP eye drops prevent corneal keratinization in PACAP deficient mice (85). A PACAP-derived peptide has been shown to promote corneal wound healing (87,88). PACAP given in form of eye drops not only acts directly on the surface but also passes ocular barriers and is able to induce protective effects in the retina (163,164).…”

Section: Non-neuronal Parts Of the Visual System: Cornea And Retinal mentioning

confidence: 99%

Protective Effects of PACAP in Peripheral Organs

et al. 2020

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Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide widely distributed in the nervous system, where it exerts strong neuroprotective effects. PACAP is also expressed in peripheral organs but its peripheral protective effects have not been summarized so far. Therefore, the aim of the present paper is to review the existing literature regarding the cytoprotective effects of PACAP in non-neuronal cell types, peripheral tissues, and organs. Among others, PACAP has widespread expression in the digestive system, where it shows protective effects in various intestinal pathologies, such as duodenal ulcer, small bowel ischemia, and intestinal inflammation. PACAP is present in both the exocrine and endocrine pancreas as well as liver where it reduces inflammation and steatosis by interfering with hepatic pathology related to obesity. It is found in several exocrine glands and also in urinary organs, where, with its protective effects being mainly published regarding renal pathologies, PACAP is protective in numerous conditions. PACAP displays anti-inflammatory effects in upper and lower airways of the respiratory system. In the skin, it is involved in the development of inflammatory pathology such as psoriasis and also has anti-allergic effects in a model of contact dermatitis. In the non-neuronal part of the visual system, PACAP showed protective effects in pathological conditions of the cornea and retinal pigment epithelial cells. The positive role of PACAP has been demonstrated on the formation and healing processes of cartilage and bone where it also prevents osteoarthritis and rheumatoid arthritis development. The protective role of PACAP was also demonstrated in the cardiovascular system in different pathological processes including hyperglycaemia-induced endothelial dysfunction and age-related vascular changes. In the heart, PACAP protects against ischemia, oxidative stress, and cardiomyopathies. PACAP is also involved in the protection against the development of pre-senile systemic amyloidosis, which is presented in various peripheral organs in PACAP-deficient mice. The studies summarized here provide strong evidence for the cytoprotective effects of the peptide. The survival-promoting effects of PACAP depend on a number of factors which are also shortly discussed in the present review.

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“…PACAP binds to three G-protein coupled receptors, a higher affinity PACAP-specific receptor (PAC1), and two VIP/PACAP receptors (VPAC1 and VPAC2) with similar affinity for VIP and PACAP ( 34 ). PACAP has been found to be involved in neuroprotection, prevents apoptosis ( 35 , 36 ), promotes cell proliferation ( 37 ), neurogenesis and axonal regeneration in the central and peripheral nervous systems ( 38 , 39 ), and modulates immune and inflammatory responses ( 40 , 41 ). We previously reported that PACAP is secreted by sympathetic nerve endings projected into the BM, and can modulate HSPCs proliferation via PAC1 signaling ( 42 ).…”

Section: Introductionmentioning

confidence: 99%

PAC1 Receptor Mediates Electroacupuncture-Induced Neuro and Immune Protection During Cisplatin Chemotherapy

Huang

Guo

et al. 2021

Front. Immunol.

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Platinum-based chemotherapy is an effective treatment used in multiple tumor treatments, but produces severe side effects including neurotoxicity, anemia, and immunosuppression, which limits its anti-tumor efficacy and increases the risk of infections. Electroacupuncture (EA) is often used to ameliorate these side effects, but its mechanism is unknown. Here, we report that EA on ST36 and SP6 prevents cisplatin-induced neurotoxicity and immunosuppression. EA induces neuroprotection, prevents pain-related neurotoxicity, preserves bone marrow (BM) hematopoiesis, and peripheral levels of leukocytes. EA activates sympathetic BM terminals to release pituitary adenylate cyclase activating polypeptide (PACAP). PACAP-receptor PAC1-antagonists abrogate the effects of EA, whereas PAC1-agonists mimic EA, prevent neurotoxicity, immunosuppression, and preserve BM hematopoiesis during cisplatin chemotherapy. Our results indicate that PAC1-agonists may provide therapeutic advantages during chemotherapy to treat patients with advanced neurotoxicity or neuropathies limiting EA efficacy.

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The PACAP-derived peptide MPAPO facilitates corneal wound healing by promoting corneal epithelial cell proliferation and trigeminal ganglion cell axon regeneration

Cited by 19 publications

References 54 publications

Distribution of PACAP and PAC1 Receptor in the Human Eye

Distribution of PACAP and PAC1 Receptor in the Human Eye

Protective Effects of PACAP in Peripheral Organs

PAC1 Receptor Mediates Electroacupuncture-Induced Neuro and Immune Protection During Cisplatin Chemotherapy

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