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Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 19417

Special Issue Editor

Dr. Dora Reglodi

E-Mail Website
Guest Editor
Department of Anatomy, MTA-PTE PACAP Research Team, Centre for Neuroscience, Szentagothai Research Centre, University of Pecs Medical School, Szigeti ut 12, H-7624 Pecs, Hungary
Interests: PACAP; apoptosis; inflammation; cellular protection; vip; secretin; glucagon
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide discovered more than thirty years ago from hypothalamic extracts. It belongs to a big peptide family, the vasoactive intestinal peptide (VIP), secretin, glucagon peptide family, acting through G protein-coupled receptors. Early studies already pointed out the robust neurotrophic and neuroprotective effects of PACAP in vitro and in vivo through a combination of antiapototic, anti-inflammatory, and antioxidant effects. Although originally isolated from the central nervous system, and although early studies showed highest concentration in the brain, PACAP also has a very widespread occurrence in peripheral organs. Numerous studies have provided proof that PACAP exerts trophic and protective effects not only in the nervous system but also in several peripheral cell types and organs. The general cytoprotective effects of the peptide also point to the potential of PACAP as a therapeutic agent in numerous toxic, traumatic or ischemic injuries of different cells and tissues. Related peptides, especially VIP, have also been proven to act as protective factors in different cellular and animal models.

The aim of this Special Issue is to gather original and review papers on the general cytoprotective effects of PACAP and related peptides. In vitro, in vivo, and human studies with potential medical importance are all welcome.

Dr. Dora Reglodi
Guest Editor

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Keywords

  • PACAP
  • apoptosis
  • inflammation
  • cellular protection
  • vip
  • secretin
  • glucagon

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Published Papers (6 papers)

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Research

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25 pages, 39327 KiB  
Article
PACAP and VIP Modulate LPS-Induced Microglial Activation and Trigger Distinct Phenotypic Changes in Murine BV2 Microglial Cells
by Jocelyn Karunia, Aram Niaz, Mawj Mandwie, Sarah Thomas Broome, Kevin A. Keay, James A. Waschek, Ghaith Al-Badri and Alessandro Castorina
Int. J. Mol. Sci. 2021, 22(20), 10947; https://doi.org/10.3390/ijms222010947 - 11 Oct 2021
Cited by 13 | Viewed by 2881
Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related immunosuppressive peptides. However, the underlying mechanisms through which these peptides regulate microglial activity are not fully understood. Using lipopolysaccharide (LPS) to induce an inflammatory challenge, we tested whether PACAP [...] Read more.
Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two structurally related immunosuppressive peptides. However, the underlying mechanisms through which these peptides regulate microglial activity are not fully understood. Using lipopolysaccharide (LPS) to induce an inflammatory challenge, we tested whether PACAP or VIP differentially affected microglial activation, morphology and cell migration. We found that both peptides attenuated LPS-induced expression of the microglial activation markers Iba1 and iNOS (### p < 0.001), as well as the pro-inflammatory mediators IL-1β, IL-6, Itgam and CD68 (### p < 0.001). In contrast, treatment with PACAP or VIP exerted distinct effects on microglial morphology and migration. PACAP reversed LPS-induced soma enlargement and increased the percentage of small-sized, rounded cells (54.09% vs. 12.05% in LPS-treated cells), whereas VIP promoted a phenotypic shift towards cell subpopulations with mid-sized, spindle-shaped somata (48.41% vs. 31.36% in LPS-treated cells). Additionally, PACAP was more efficient than VIP in restoring LPS-induced impairment of cell migration and the expression of urokinase plasminogen activator (uPA) in BV2 cells compared with VIP. These results suggest that whilst both PACAP and VIP exert similar immunosuppressive effects in activated BV2 microglia, each peptide triggers distinctive shifts towards phenotypes of differing morphologies and with differing migration capacities. Full article
(This article belongs to the Special Issue Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides)
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13 pages, 2211 KiB  
Article
Retinoprotective Effects of PACAP Eye Drops in Microbead-Induced Glaucoma Model in Rats
by Edina Szabo, Evelin Patko, Alexandra Vaczy, Dorottya Molitor, Adrienne Csutak, Gabor Toth, Dora Reglodi and Tamas Atlasz
Int. J. Mol. Sci. 2021, 22(16), 8825; https://doi.org/10.3390/ijms22168825 - 17 Aug 2021
Cited by 12 | Viewed by 2355
Abstract
Glaucoma is associated with increased intraocular pressure (IOP), causing the apoptosis of retinal ganglion cells (RGCs) and the loss of their axons leading to blindness. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in several neural injuries, including retinopathies. The aim of this [...] Read more.
Glaucoma is associated with increased intraocular pressure (IOP), causing the apoptosis of retinal ganglion cells (RGCs) and the loss of their axons leading to blindness. Pituitary adenylate cyclase activating polypeptide (PACAP) is neuroprotective in several neural injuries, including retinopathies. The aim of this study was to investigate the effects of PACAP1-38 eye drops in a model of glaucoma. IOP was elevated bilaterally by injections of microbeads to block the aqueous humor outflow. The control groups received the same volume of saline. Animals were treated with PACAP1-38 (1 µg/drop, 3 × 1 drop/day) or vehicle for 4 weeks starting one day after the injections. Retinal morphology by histology and optical coherence tomography, function by electroretinography, and IOP changes were analyzed. Animals were sacrificed 8 weeks after the injections. Microbeads injections induced a significant increase in the IOP, while PACAP1-38 treatment lowered it to normal levels (~10 mmHg). Significant retinal degeneration and functional impairment were observed in the microbead-injected group without PACAP1-38 treatment. In the microbeads + PACAP1-38 group, the retinal morphology and functionality were close to the normal values. In summary, our results show that PACAP1-38, given in form of eye drops, is neuroprotective in glaucoma, providing the basis for potential future therapeutic administration. Full article
(This article belongs to the Special Issue Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides)
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19 pages, 2488 KiB  
Article
PACAP-38 in Acute ST-Segment Elevation Myocardial Infarction in Humans and Pigs: A Translational Study
by Dora Szabo, Zsolt Sarszegi, Beata Polgar, Eva Saghy, Adam Nemeth, Dora Reglodi, Andras Makkos, Aniko Gorbe, Zsuzsanna Helyes, Peter Ferdinandy, Robert Herczeg, Attila Gyenesei, Attila Cziraki and Andrea Tamas
Int. J. Mol. Sci. 2021, 22(6), 2883; https://doi.org/10.3390/ijms22062883 - 12 Mar 2021
Cited by 11 | Viewed by 2619
Abstract
Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a [...] Read more.
Acute myocardial infarction (MI) is one of the most common causes of death worldwide. Pituitary adenylate cyclase activating polypeptide (PACAP) is a cardioprotective neuropeptide expressing its receptors in the cardiovascular system. The aim of our study was to examine tissue PACAP-38 in a translational porcine MI model and plasma PACAP-38 levels in patients with ST-segment elevation myocardial infarction (STEMI). Significantly lower PACAP-38 levels were detected in the non-ischemic region of the left ventricle (LV) in MI heart compared to the ischemic region of MI-LV and also to the Sham-operated LV in porcine MI model. In STEMI patients, plasma PACAP-38 level was significantly higher before percutaneous coronary intervention (PCI) compared to controls, and decreased after PCI. Significant negative correlation was found between plasma PACAP-38 and troponin levels. Furthermore, a significant effect was revealed between plasma PACAP-38, hypertension and HbA1c levels. This was the first study showing significant changes in cardiac tissue PACAP levels in a porcine MI model and plasma PACAP levels in STEMI patients. These results suggest that PACAP, due to its cardioprotective effects, may play a regulatory role in MI and could be a potential biomarker or drug target in MI. Full article
(This article belongs to the Special Issue Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides)
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15 pages, 1727 KiB  
Article
Age and Sex-Dependent ADNP Regulation of Muscle Gene Expression Is Correlated with Motor Behavior: Possible Feedback Mechanism with PACAP
by Oxana Kapitansky, Shlomo Sragovich, Iman Jaljuli, Adva Hadar, Eliezer Giladi and Illana Gozes
Int. J. Mol. Sci. 2020, 21(18), 6715; https://doi.org/10.3390/ijms21186715 - 14 Sep 2020
Cited by 17 | Viewed by 3804
Abstract
The activity-dependent neuroprotective protein (ADNP), a double-edged sword, sex-dependently regulates multiple genes and was previously associated with the control of early muscle development and aging. Here we aimed to decipher the involvement of ADNP in versatile muscle gene expression patterns in correlation with [...] Read more.
The activity-dependent neuroprotective protein (ADNP), a double-edged sword, sex-dependently regulates multiple genes and was previously associated with the control of early muscle development and aging. Here we aimed to decipher the involvement of ADNP in versatile muscle gene expression patterns in correlation with motor function throughout life. Using quantitative RT-PCR we showed that Adnp+/− heterozygous deficiency in mice resulted in aberrant gastrocnemius (GC) muscle, tongue and bladder gene expression, which was corrected by the Adnp snippet, drug candidate, NAP (CP201). A significant sexual dichotomy was discovered, coupled to muscle and age-specific gene regulation. As such, Adnp was shown to regulate myosin light chain (Myl) in the gastrocnemius (GC) muscle, the language acquisition gene forkhead box protein P2 (Foxp2) in the tongue and the pituitary-adenylate cyclase activating polypeptide (PACAP) receptor PAC1 mRNA (Adcyap1r1) in the bladder, with PACAP linked to bladder function. A tight age regulation was observed, coupled to an extensive correlation to muscle function (gait analysis), placing ADNP as a muscle-regulating gene/protein. Full article
(This article belongs to the Special Issue Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides)
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16 pages, 2831 KiB  
Article
Alzheimer’s Disease Mouse as a Model of Testis Degeneration
by Vince Szegeczki, Gabriella Horváth, Helga Perényi, Andrea Tamás, Zsolt Radák, Dóra Ábrahám, Róza Zákány, Dora Reglodi and Tamás Juhász
Int. J. Mol. Sci. 2020, 21(16), 5726; https://doi.org/10.3390/ijms21165726 - 10 Aug 2020
Cited by 7 | Viewed by 2977
Abstract
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with protective functions in the central nervous system and various peripheral organs. PACAP has the highest expression level in the testes, among the peripheral organs, and has a positive regulative role in spermatogenesis and [...] Read more.
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide with protective functions in the central nervous system and various peripheral organs. PACAP has the highest expression level in the testes, among the peripheral organs, and has a positive regulative role in spermatogenesis and in sperm motility. In the present study, we explored testicular degenerative alterations in a mouse model of Alzheimer’s disease (AD) (B6C3-Tg(APPswe,PSEN1dE9)85Dbo/J) and demonstrated changes in PACAP-regulated signaling pathways. In addition, the effects of increased physical activity of AD (trained AD (TAD)) mice on testis were also followed. Reduced cell number and decreased thickness of basement membrane were detected in AD samples. These changes were compensated by physical activity. Expression of PACAP receptors and canonical signaling elements such as PKA, P-PKA, PP2A significantly decreased in AD mice, and altered Sox transcription factor expression was also detected. Via this signaling mechanism, physical activity compensated the negative effects of AD on the expression of type IV collagen. Our findings suggest that the testes of AD mice can be a good model of testis degeneration. Moreover, it can be an appropriate organ to follow the effects of various interventions such as physical activity on tissue regeneration and signaling alterations. Full article
(This article belongs to the Special Issue Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides)
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Review

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14 pages, 1424 KiB  
Review
Effects of PACAP on Schwann Cells: Focus on Nerve Injury
by Grazia Maugeri, Agata Grazia D’Amico, Giuseppe Musumeci, Dora Reglodi and Velia D’Agata
Int. J. Mol. Sci. 2020, 21(21), 8233; https://doi.org/10.3390/ijms21218233 - 3 Nov 2020
Cited by 41 | Viewed by 3960
Abstract
Schwann cells, the most abundant glial cells of the peripheral nervous system, represent the key players able to supply extracellular microenvironment for axonal regrowth and restoration of myelin sheaths on regenerating axons. Following nerve injury, Schwann cells respond adaptively to damage by acquiring [...] Read more.
Schwann cells, the most abundant glial cells of the peripheral nervous system, represent the key players able to supply extracellular microenvironment for axonal regrowth and restoration of myelin sheaths on regenerating axons. Following nerve injury, Schwann cells respond adaptively to damage by acquiring a new phenotype. In particular, some of them localize in the distal stump to form the Bungner band, a regeneration track in the distal site of the injured nerve, whereas others produce cytokines involved in recruitment of macrophages infiltrating into the nerve damaged area for axonal and myelin debris clearance. Several neurotrophic factors, including pituitary adenylyl cyclase-activating peptide (PACAP), promote survival and axonal elongation of injured neurons. The present review summarizes the evidence existing in the literature demonstrating the autocrine and/or paracrine action exerted by PACAP to promote remyelination and ameliorate the peripheral nerve inflammatory response following nerve injury. Full article
(This article belongs to the Special Issue Cytoprotective Effects of Pituitary Adenylate Cyclase Activating Polypeptide (PACAP) and Related Peptides)
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