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Aging and disease    2020, Vol. 11 Issue (6) : 1496-1512     DOI: 10.14336/AD.2020.0626
Review Article |
Pituitary Adenylate Cyclase-Activating Polypeptide: A Promising Neuroprotective Peptide in Stroke
Yuanjian Fang1, Reng Ren1, Hui Shi2, Lei Huang3,4, Cameron Lenahan3,4,5, Qin Lu6, Lihui Tang1, Yi Huang1, Jiping Tang3,4,7, Jianmin Zhang1,*, John H Zhang3,4,7,*
1Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
2Department of Neurosurgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
3Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA.
4Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
5Burrell College of Osteopathic Medicine, Las Cruces, NM, USA.
6Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
7Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA.
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The search for viable, effective treatments for acute stroke continues to be a global priority due to the high mortality and morbidity. Current therapeutic treatments have limited effects, making the search for new treatments imperative. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a well-established cytoprotective neuropeptide that participates in diverse neural physiological and pathological activities, such as neuronal proliferation, differentiation, and migration, as well as neuroprotection. It is considered a promising treatment in numerous neurological diseases. Thus, PACAP bears potential as a new therapeutic strategy for stroke treatment. Herein, we provide an overview pertaining to the current knowledge of PACAP, its receptors, and its potential neuroprotective role in the setting of stroke, as well as various mechanisms of neuroprotection involving ionic homeostasis, excitotoxicity, cell edema, oxidative stress, inflammation, and cell death, as well as the route of PACAP administration.

Keywords stroke      pituitary adenylate cyclase activating polypeptide      cerebral ischemia      intracerebral hemorrhage      subarachnoid hemorrhage     
Corresponding Authors: Zhang Jianmin,Zhang John H   
About author:

These authors contrinuted equally to this work.

Just Accepted Date: 02 July 2020   Issue Date: 19 November 2020
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Fang Yuanjian
Ren Reng
Shi Hui
Huang Lei
Lenahan Cameron
Lu Qin
Tang Lihui
Huang Yi
Tang Jiping
Zhang Jianmin
Zhang John H
Cite this article:   
Fang Yuanjian,Ren Reng,Shi Hui, et al. Pituitary Adenylate Cyclase-Activating Polypeptide: A Promising Neuroprotective Peptide in Stroke[J]. Aging and disease, 2020, 11(6): 1496-1512.
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Figure 1.  Schematic pathway of PACAP signaling cascades. PACAP exerts function via activation of three different G-protein coupled receptors: PAC1, VPAC1, and VPAC2. The PAC1 has a 100-fold selectivity for PACAP over VIP, contributing to its role as the main functional receptor of PACAP. Each PACAP receptor is coupled primarily to Gs or Gq, which stimulate AC and PLC activation. In the AC-involved signaling pathway, AC accelerates ATP conversion to cAMP, which then prompts PKA phosphorylation and activation of EPAC pathway. In contrast, activation of PLC boosts the PKC pathway, and the IP3 activation to increase the intracellular Ca2+. Both PLC and AC/cAMP signaling pathways are related to the PACAP function by mediating downstream targets, such as the MAPKs family and the PI3K/Akt pathway. These pathways further mediate cell proliferation, differentiation migration, and survival through several nuclear genes, such as CREB, NF-kB, JAK and cJun. Besides, these downstream signaling pathways also appear to be directly activated by PAC1 and are paralleled with PLC and AC/cAMP pathway in some cells.
Figure 2.  Current and proposed function of PACAP in different pathophysiology after stroke. PACAP is a promising neuroprotective peptide with great potential to mediate ionic homeostasis, cerebral edema formation, cytotoxicity, oxidative/nitrosative stress, inflammation, cell death, and BBB function after stroke.
RoutesStarting timeDurationBest dosage
1996Uchida D.[15]RatsTransient global ischemiai.c.v.
Post-surgery and post-24h
16pmol/h and 160pmol/h
1998Somogyvari-vigh A.[172]RatsTransient global ischemiai.v.Post-24hSingle with continuous5nmol/kg with 160pmol/h
1998Shioda F.[43]RatsTransient global ischemiai.c.v.Pre-48hContinuous1pmol/h
2000Reglodi D.[98]RatstMCAOi.v.Post-6hSingle with continuous20nmol/kg with 160pmol/h
2000Reglodi D.[99]RatstMCAOi.v.Post-4h, 8h, 12hSingle with continuous5nmol/rat with 160pmol/h
2002Dohi K.[44]RatstMCAOi.c.v.Pre-48hContinuous1pmol/h
2002Yan D.[114]RatsTransient global ischemiai.c.v.Pre-15minSingle10nmol/rat
2002Tamas A.[96]RatspMCAOi.c.v.Pre-surgerySingle450pmol/rat
2002&2004Reglodi D.[157, 171]RatspMCAOi.c.v.Pre-surgerySingle2μg/rat
2006Chen Y.[97]MicepMCAOi.c.v.
2009Lenti L.[130]Newborn pigsCO2 ventilation induced transient global ischemiaDirective exposePre-CO2 ventilationContinuous10pmol/L
2010Stetler RA.[141]RatsTransient global ischemiai.c.v.Pre-24, 12, 6hSingle200pmol/rat
2012Lazarovici P.,[156]RatstMCAOi.v.Post-2hSingle30ng/kg
2012Nakamachi T.[152]MiceTransient global ischemiai.c.v.Post-surgerySingle1pmol/mice
2014Hori M. et. al.[153]MicepMCAOi.c.v.Post-surgerySingle1pmol/mice
2014Lin C. et al.[93]RatsTransient global ischemiai.p.Post-4hSingle10μg/kg
2015Brifault C.[154]MicepMCAOi.c.v.Post-72hSinglePACAP-producing-stem cell
Table 1  The approaches of PACAP38 administration in stroke.
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