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      A Novel Octapeptide Derived From G Protein-Coupled Receptor 124 Improves Cognitive Function Via Pro-Angiogenesis In A Rat Model Of Chronic Cerebral Hypoperfusion-Induced Vascular Dementia


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          The lack of effective therapies mandates the development of new treatment strategies for vascular dementia (VaD). G protein-coupled receptor 124 (GPR124) may be a therapeutic target for angiogenesis-related diseases of CNS, including VaD. The GCPF peptide is a truncated and screened fragment of the GPR124 extracellular domain. The potential use of GCPF for VaD treatment, angiogenesis and targeting of integrin αvβ3 are evaluated.

          Methods and results

          First, the in vivo results indicated that the GCPF peptide could decrease mean escape latency and increase platform crossing times in BCCAO rats. Second, the in vitro and ex vivo results indicated that the GCPF peptide was an active angiogenic peptide and could promote hCMEC/D3 cell migration and adhesion to ECM molecules. Third, in silico analyses predicted that GCPF could specifically interact with integrin αvβ3; the ∆G of GCPF binding to the binding pocket was −16.402 KJ/mol. The molecular characteristics indicated that highly hydrophilic GCPF with a pI of 11.70 had a short half-life in mammals (~1 hr). Finally, the ELISA experiments indicated that low dissociation constant (K d= 2.412±0.455 nM) corresponds to the high affinity of GCPF for integrin αvβ3.


          The data indicate that adhesion of GCPF immobilized on ECM surface to endothelial cells via integrin αvβ3 modulates cellular functions to promote angiogenesis and improve cognitive function. This is the first report to prove that GCPF, a novel octapeptide, may be an effective strategy for VaD therapy.

          Most cited references25

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          Place navigation impaired in rats with hippocampal lesions

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            Crystal structure of the extracellular segment of integrin alpha Vbeta3 in complex with an Arg-Gly-Asp ligand.

            The structural basis for the divalent cation-dependent binding of heterodimeric alphabeta integrins to their ligands, which contain the prototypical Arg-Gly-Asp sequence, is unknown. Interaction with ligands triggers tertiary and quaternary structural rearrangements in integrins that are needed for cell signaling. Here we report the crystal structure of the extracellular segment of integrin alphaVbeta3 in complex with a cyclic peptide presenting the Arg-Gly-Asp sequence. The ligand binds at the major interface between the alphaV and beta3 subunits and makes extensive contacts with both. Both tertiary and quaternary changes are observed in the presence of ligand. The tertiary rearrangements take place in betaA, the ligand-binding domain of beta3; in the complex, betaA acquires two cations, one of which contacts the ligand Asp directly and the other stabilizes the ligand-binding surface. Ligand binding induces small changes in the orientation of alphaV relative to beta3.
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              Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases.

              Chronic cerebral hypoperfusion has been associated with cognitive decline in aging and Alzheimer's disease. Moreover, the pattern of cerebral blood flow in mild cognitive impairment has emerged as a predictive marker for the progression into Alzheimer's disease. The reconstruction of a pathological condition in animal models is a suitable approach to the unraveling of causal relationships. For this reason, permanent, bilateral occlusion of the common carotid arteries (2VO) in rats has been established as a procedure to investigate the effects of chronic cerebral hypoperfusion on cognitive dysfunction and neurodegenerative processes. Over the years, the 2VO model has generated a large amount of data, revealing the 2VO-related pattern of cerebral hypoperfusion and metabolic changes, learning and memory disturbances, failure of neuronal signaling, and the neuropathological changes in the hippocampus. In addition, the model has been introduced in research into ischemic white matter injury and ischemic eye disease. The present survey sets out to provide a comprehensive summary of the achievements made with the 2VO model, and a critical evaluation and integration of the various results, and to relate the experimental data to human diseases. The data that have accumulated from use of the 2VO model in the rat permit an understanding of the causative role played by cerebral hypoperfusion in neurodegenerative diseases. Thorough characterization of the model suggests that 2VO in the rat is suitable for the development of potentially neuroprotective strategies in neurodegenerative diseases.

                Author and article information

                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                23 October 2019
                : 13
                : 3669-3682
                [1 ]College of Science, China Pharmaceutical University , Nanjing, People’s Republic of China
                [2 ]Neuro-Psychiatric Institute, Nanjing Medical University Affiliated Brain Hospital , Nanjing, People’s Republic of China
                [3 ]School of Pharmacy, Nanjing Medical University , Nanjing, Nanjing, People’s Republic of China
                [4 ]Department of Geriatric Neurology, Nanjing Medical University Affiliated Brain Hospital , Nanjing, People’s Republic of China
                Author notes
                Correspondence: Hong Shen; Hong Xiao Neuro-Psychiatric Institute, Nanjing Medical University Affiliated Brain Hospital , 264# Guangzhou Road, Nanjing210029, People’s Republic of ChinaTel +86 25 8229 6334; +86 25 8229 6352 Email shenhong_nbh@njmu.edu.cn; xhnkyy123@163.com
                © 2019 Xiao et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                : 08 August 2019
                : 02 October 2019
                Page count
                Figures: 8, References: 36, Pages: 14
                Original Research

                Pharmacology & Pharmaceutical medicine
                g-protein coupled receptor 124,vascular dementia,chronic cerebral hypoperfusion,angiogenesis,integrin,protein therapy


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