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      Pituitary Adenylate Cyclase-Activating Polypeptide: A Promising Neuroprotective Peptide in Stroke

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          Abstract

          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.

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          Most cited references172

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          An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association.

          Despite the global impact and advances in understanding the pathophysiology of cerebrovascular diseases, the term "stroke" is not consistently defined in clinical practice, in clinical research, or in assessments of the public health. The classic definition is mainly clinical and does not account for advances in science and technology. The Stroke Council of the American Heart Association/American Stroke Association convened a writing group to develop an expert consensus document for an updated definition of stroke for the 21st century. Central nervous system infarction is defined as brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and/or clinical evidence of permanent injury. Central nervous system infarction occurs over a clinical spectrum: Ischemic stroke specifically refers to central nervous system infarction accompanied by overt symptoms, while silent infarction by definition causes no known symptoms. Stroke also broadly includes intracerebral hemorrhage and subarachnoid hemorrhage. The updated definition of stroke incorporates clinical and tissue criteria and can be incorporated into practice, research, and assessments of the public health.
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            Sterile inflammation: sensing and reacting to damage.

            Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.
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              Temporal and spatial dynamics of cerebral immune cell accumulation in stroke.

              Ischemic stroke leads to significant morbidity and mortality in the Western world. Early reperfusion strategies remain the treatment of choice but can initiate and augment an inflammatory response causing secondary brain damage. The understanding of postischemic inflammation is very limited. The objectives of this study were to define the temporal and spatial infiltration of immune cell populations and their activation patterns in a murine cerebral ischemia-reperfusion injury model. Transient middle cerebral artery occlusion was induced for 1 hour followed by 12-hour to 7-day reperfusion in C57/BL6 mice. Immunohistochemistry and flow cytometry were used to quantify the infiltrating immune cell subsets. Accumulation of microglia and infiltration of the ischemic hemisphere by macrophages, lymphocytes, and dendritic cells (DCs) preceded the neutrophilic influx. DCs were found to increase 20-fold and constituted a substantial proportion of infiltrating cells. DCs exhibited a significant upregulation of major histocompatibility complex II and major histocompatibility complex II high-expressing DCs were found 100 times more abundant than in sham conditions. Upregulation of the costimulatory molecule CD80 was observed in DCs and microglial cells but did not further increase in major histocompatibility complex II high-expressing DCs. No lymphocyte activation was observed. Additionally, regulatory immune cells (natural killer T-cells, CD4(-)/CD8(-)T lymphocytes) cumulated in the ischemic hemisphere. This study provides a detailed analysis of the temporal dynamics of immune cell accumulation in a rodent stroke model. The peculiar activation pattern and massive increase of antigen-presenting cells in temporal conjunction with regulatory cells might provide additional insight into poststroke immune regulation.
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                Author and article information

                Journal
                Aging Dis
                Aging Dis
                Aging and Disease
                JKL International LLC
                2152-5250
                December 2020
                1 December 2020
                : 11
                : 6
                : 1496-1512
                Affiliations
                [1-ad-11-6-1496] 1Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China.
                [2-ad-11-6-1496] 2Department of Neurosurgery, Yongchuan Hospital, Chongqing Medical University, Chongqing, China.
                [3-ad-11-6-1496] 3Department of Neurosurgery, Loma Linda University, Loma Linda, CA, USA.
                [4-ad-11-6-1496] 4Department of Physiology and Pharmacology, Loma Linda University, Loma Linda, CA, USA.
                [5-ad-11-6-1496] 5Burrell College of Osteopathic Medicine, Las Cruces, NM, USA.
                [6-ad-11-6-1496] 6Department of Neurosurgery, Sir Run Run Shaw Hospital, Zhejiang University, School of Medicine, Hangzhou, Zhejiang, China.
                [7-ad-11-6-1496] 7Department of Anesthesiology, Loma Linda University, Loma Linda, CA, USA.
                Author notes
                [* ]Correspondence should be addressed to: Dr. John H. Zhang, Loma Linda University, Loma Linda, CA 92354, USA. Email: johnzhang3910@ 123456yahoo.com ; Dr. Jianmin Zhang, Hangzhou, 310009, Zhejiang, China. Email: zjm135@ 123456zju.edu.cn
                Article
                ad-11-6-1496
                10.14336/AD.2020.0626
                7673855
                33269103
                8a0cfce4-e895-4e94-a588-6af725998e7b
                copyright: © 2020 Fang et al.

                this is an open access article distributed under the terms of the creative commons attribution license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                History
                : 2 June 2020
                : 25 June 2020
                : 26 June 2020
                Categories
                Review Article

                stroke,pituitary adenylate cyclase activating polypeptide,cerebral ischemia,intracerebral hemorrhage,subarachnoid hemorrhage

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