Targeting Rap1b signaling cascades with CDNF: Mitigating platelet activation, plasma oxylipins and reperfusion injury in stroke.

Autor:	Wu JS; Department of Biology and Anatomy, National Defense Medical Center, Taipei 114, Taiwan., Lõhelaid H; Neuroscience Center, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland., Shih CC; Department of Pharmacology, National Defense Medical Center, Taipei 114, Taiwan., Liew HK; PhD Program in Pharmacology and Toxicology, Tzu Chi University, 970 Hualien County, Hualien, Taiwan; Neuro-Medical Scientific Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 970 Hualien County, Hualien, Taiwan; Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 970 Hualien County, Hualien, Taiwan., Wang V; Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan., Hu WF; PhD Program in Pharmacology and Toxicology, Tzu Chi University, 970 Hualien County, Hualien, Taiwan., Chen YH; Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan., Saarma M; Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland., Airavaara M; Neuroscience Center, HiLIFE, University of Helsinki, 00014 Helsinki, Finland; Faculty of Pharmacy, University of Helsinki, 00014 Helsinki, Finland., Tseng KY; Department of Neurological Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei 114, Taiwan. Electronic address: neuronsurgery@gmail.com.
Jazyk:	angličtina
Zdroj:	Molecular therapy : the journal of the American Society of Gene Therapy [Mol Ther] 2024 Nov 06; Vol. 32 (11), pp. 4021-4044. Date of Electronic Publication: 2024 Sep 10.
DOI:	10.1016/j.ymthe.2024.09.005
Abstrakt:	Cerebral reperfusion injury in stroke, stemming from interconnected thrombotic and inflammatory signatures, often involves platelet activation, aggregation and its interaction with various immune cells, contributing to microvascular dysfunction. However, the regulatory mechanisms behind this platelet activation and the resulting inflammation are not well understood, complicating the development of effective stroke therapies. Utilizing animal models and platelets from hemorrhagic stroke patients, our research demonstrates that human cerebral dopamine neurotrophic factor (CDNF) acts as an endogenous antagonist, mitigating platelet aggregation and associated neuroinflammation. CDNF moderates mitochondrial membrane potential, reactive oxygen species production, and intracellular calcium in activated platelets by interfering with GTP binding to Rap1b, thereby reducing Rap1b activation and downregulating the Rap1b-MAPK-PLA2 signaling pathway, which decreases release of the pro-inflammatory mediator thromboxane A2. In addition, CDNF reduces the inflammatory response in BV2 microglial cells co-cultured with activated platelets. Consistent with ex vivo findings, subcutaneous administration of CDNF in a rat model of ischemic stroke significantly reduces platelet activation, aggregation, lipid mediator production, infarct volume, and neurological deficits. In summary, our study highlights CDNF as a promising therapeutic target for mitigating platelet-induced inflammation and enhancing recovery in stroke. Harnessing the CDNF pathway may offer a novel therapeutic strategy for stroke intervention. Competing Interests: Declaration of interests M.S. is one of inventors of the CDNF-related patent (7452969), which is owned by the Herantis Pharma Company (Espoo, Finland). (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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