Delving into the Latest Updates on PACAP-38 with Synapse

Overview

Basic Info

Drug Type

Recombinant polypeptide

Synonyms

PACAP, Pituitary adenylate cyclase activating polypeptide

+ [3]

Target

AC

Mechanism

AC stimulants(Adenylate cyclase stimulants)

Therapeutic Areas

Immune System DiseasesNervous System DiseasesCardiovascular Diseases+ [3]

Active Indication-

Inactive Indication

AsthmaCardiotoxicity drug-inducedNon-Small Cell Lung Cancer+ [1]

Originator Organization

Tulane University Hospital & Clinic

Active Organization-

Inactive Organization

National Institutes of Health

Endo International Plc

Tulane University Hospital & Clinic

Drug Highest PhaseDiscontinuedPhase 1

First Approval Date-

Regulation-

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AbstractEvidence has been accumulating that elements of the vertebrate pituitary adenylate cyclase-activating polypeptide (PACAP) system are missing in non-chordate genomes, which is at odds with the partial sequence-, immunohistochemical-, and physiological data in the literature. Multilevel experiments were performed on the great pond snail (Lymnaea stagnalis) to explore the role of PACAP in invertebrates. Screening of neuronal transcriptome and genome data did not reveal homologs to the elements of vertebrate PACAP system. Despite this, immunohistochemical investigations with an anti-human PAC1 receptor antibody yielded a positive signal in the neuronal elements in the heart. Although Western blotting of proteins extracted from the nervous system found a relevant band for PACAP-38, immunoprecipitation and mass spectrometric analyses revealed no corresponding peptide fragments. Similarly to the effects reported in vertebrates, PACAP-38 significantly increased cAMP synthesis in the heart and had a positive ionotropic effect on heart preparations. Moreover, it significantly modulated the effects of serotonin and acetylcholine. Homologs to members of Cluster B receptors, which have shared common evolutionary origin with the vertebrate PACAP receptors, PTHRs, and GCGRs, were identified and shown not to be expressed in the heart, which does not support a potential role in the mediation of PACAP-induced effects. Our findings support the notion that the PACAP system emerged after the protostome-deuterostome divergence. Using antibodies against vertebrate proteins is again highlighted to have little/no value in invertebrate studies. The physiological effects of vertebrate PACAP peptides in protostomes, no matter how similar they are to those in vertebrates, should be considered non-specific.

01 Oct 2024·Biomedicine & Pharmacotherapy

Injectable Gel-PEG hydrogels as promising delivery system for intravitreal PACAP release: Novel therapeutics for unilateral common carotid artery occlusion induced retinal ischemia

Article

Author: Yang, Yuan ; Shu, Qin ; Nie, WanQin ; Ju, YaHan ; Liang, XiaoYi ; Guo, YongLin ; Yang, XueFeng ; Gu, Ping ; Chen, XiRui ; Li, Lin ; Li, XiaoJing ; Chen, MoXin

Retinal ischemia is an ophthalmic emergency often caused by cardiovascular diseases, leading to irreversible vision loss and even blindness. Innovative retinal ischemia treatments are needed due to limited options. The pathological mechanisms involve retinal cell apoptosis and microglial activation. The pituitary adenylate cyclase-activating polypeptide (PACAP) is a well distributed neuropeptide found in both central nervous system and peripheral organs. Though it shows great anti-apoptosis and anti-microglia activation properties, it is rapidly cleared by intravitreal injection. Herein, we established a novel poly(ethylene glycol) (PEG) hydrogel system by cross-linking 4arm-PEG-NHS and 4arm-PEG-NH₂ to load PACAP (PACAP@Gel-PEG), which exhibited great fluidity, injectability, structural recovery ability, moderate swelling ratio and drug release ability that were appropriate for drug delivery. Then the safety and effectiveness of the PACAP@Gel-PEG were evaluated in vitro in three retinal cell lines (ARPE-19, 661 W and rRMC) and in vivo using the unilateral common carotid artery occlusion (UCCAO) mice model. The CCK-8 test and live/dead staining demonstrated that PACAP@Gel-PEG exhibited excellent biocompatibility in three retinal cell lines. Furthermore, after PACAP@Gel-PEG treatment, a great anti-apoptotic effect was observed in cells treated by CoCl₂. Application of PACAP@Gel-PEG greatly improved the therapeutic efficacy of PACAP in restoring retinal function, maintaining retinal integrity, and suppressing apoptosis and microglia activation in retinal tissues. Moreover, in mice, the biosafety of PACAP@Gel-PEG was confirmed by H&E staining of systemic organs. Taken together, our results demonstrated PACAP@Gel-PEG as a promising therapeutic option for retinal ischemia, providing new strategies for vision restoration.

01 Aug 2024·British Journal of Pharmacology

Pharmacology of PACAP and VIP receptors in the spinal cord highlights the importance of the PAC₁ receptor

Article

Author: Rees, Tayla A ; O'Carroll, Simon J ; Walker, Christopher S ; Guo, Song ; Faull, Richard L M ; Tan, Sheryl ; Hay, Debbie L ; Curtis, Maurice A ; Tasma, Zoe ; Christensen, Sarah L

Background and PurposeThe spinal cord is a key structure involved in the transmission and modulation of pain. Pituitary adenylate cyclase‐activating peptide (PACAP) and vasoactive intestinal peptide (VIP), are expressed in the spinal cord. These peptides activate G protein‐coupled receptors (PAC1, VPAC1 and VPAC2) that could provide targets for the development of novel pain treatments. However, it is not clear which of these receptors are expressed within the spinal cord and how these receptors signal.Experimental ApproachDissociated rat spinal cord cultures were used to examine agonist and antagonist receptor pharmacology. Signalling profiles were determined for five signalling pathways. The expression of different PACAP and VIP receptors was then investigated in mouse, rat and human spinal cords using immunoblotting and immunofluorescence.Key ResultsPACAP, but not VIP, potently stimulated cAMP, IP1 accumulation and ERK and cAMP response element‐binding protein (CREB) but not Akt phosphorylation in spinal cord cultures. Signalling was antagonised by M65 and PACAP6–38. PACAP‐27 was more effectively antagonised than either PACAP‐38 or VIP. The patterns of PAC1 and VPAC2 receptor‐like immunoreactivity appeared to be distinct in the spinal cord.Conclusions and ImplicationsThe pharmacological profile in the spinal cord suggested that a PAC1 receptor is the major functional receptor subtype present and thus likely mediates the nociceptive effects of the PACAP family of peptides in the spinal cord. However, the potential expression of both PAC1 and VPAC2 receptors in the spinal cord highlights that these receptors may play differential roles and are both possible therapeutic targets.

100 Deals associated with PACAP-38

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiotoxicity drug-induced	Phase 1	US	Tulane University Hospital & Clinic	15 Jul 2017
Stroke	Phase 1	US	National Institutes of Health	15 Nov 2006
Asthma	Phase 1	-	Endo International Plc	-
Asthma	Phase 1	-	Tulane University Hospital & Clinic	-
Non-Small Cell Lung Cancer	Phase 1	-	Tulane University Hospital & Clinic	-
Non-Small Cell Lung Cancer	Phase 1	-	Endo International Plc	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


AACR2023	Not Applicable	Non-Small Cell Lung Cancer	-	PACAP-27	sstwzhpixp(gmivmoawce) = rgtclzjoog cdcxomjknv (fvfmgxdaxw )	-	04 Apr 2023
				NRG1	sstwzhpixp(gmivmoawce) = mxbcylfsxq cdcxomjknv (fvfmgxdaxw )
NCT02542605 (CTgov)	Phase 1	Migraine Disorders	35	Placebo+PACAP-38 Challenge Agent (Placebo)	lxhcpmnhkp(pijrzvyrnc) = znxylitwmr xxrfyamayr (tnewyvhhxj, ioechyxgfu - frgieaqthn) View more	-	03 Jun 2019
				Erenumab+PACAP-38 Challenge Agent (Erenumab)	lxhcpmnhkp(pijrzvyrnc) = ngpmpfjmam xxrfyamayr (tnewyvhhxj, npqqmpvjfe - eplcwyhiwm) View more
EASD2014	Not Applicable	Inflammation PACAP receptors	-	PACAP	vnmlosxaaw(dudvyvfqos) = avuzydcciu emmxpazowu (rpngffykwl, 0.5)	Positive	16 Sep 2014
				LPS	pcbbrxqwaf(dvawmjhgxa) = xmokawuzbn yvivwuryyn (uequglxojb ) View more
ASN2013	Not Applicable	-	-	PACAP	lfcrywroor(fyxzsngron) = bpkvnulwym kbnmkongez (pczuahkfxl )	-	05 Nov 2013
				PACAP1-38 agonist	lfcrywroor(fyxzsngron) = nfpicaldxy kbnmkongez (pczuahkfxl )
ASN2012	Not Applicable	Nephrosis, Congenital PACAP	4	PACAP	yyiixmymmp(nbvxgvpwsq) = increased platelet count aeptjislts (ewcoyztzwm ) View more	Positive	30 Oct 2012
ASN2010	Not Applicable	Nephrotoxicity	-	Pituitary Adenylate Cyclase-Activating Polypeptide	gjuyteopqy(skmblauwcl) = zkygmqwyoe psflzuzadh (wbslikocsw )	Positive	16 Nov 2010
				CsA + PACAP38	gjuyteopqy(skmblauwcl) = ymesvondvo psflzuzadh (wbslikocsw )