Remote ischemic conditioning attenuates blood-brain barrier disruption after recombinant tissue plasminogen activator treatment via reducing PDGF-CC. (January 2023)

• Record Type: Journal Article
• Authors: He, Qianyan; Ma, Yinzhong; Fang, Cheng; Deng, Zijun; Wang, Fang; Qu, Yang; Yin, Meifang; Zhao, Ruoyu; Zhang, Dianhui; Guo, Fuyou; Yang, Yi; Chang, Junlei; Guo, Zhen-Ni
• Is Part Of: Pharmacological research. Volume 187(2023)
• Publication Date: 2023-01
• Subjects: AIS acute ischemic stroke -- rtPA recombinant tissue plasminogen activator -- BBB blood-brain barrier -- HT hemorrhagic transformation -- PDGF platelet-derived growth factor -- RIC remote ischemic conditioning -- RIPerC remote ischemic perconditioning -- RIPreC remote ischemic preconditioning -- RIPostC remote ischemic postconditioning -- ZO-1 zonula occludens-1 -- GFAP glial fibrillary acidic protein -- HIF-1α hypoxia-inducible factor-1α; Remote ischemic conditioning -- Acute ischemic stroke -- Thromboembolic stroke -- Blood-brain barrier -- PDGF-CC -- rtPA; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2022.106641
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: Treatment of acute ischemic stroke with the recombinant tissue plasminogen activator (rtPA) is associated with increased blood–brain barrier (BBB) disruption and hemorrhagic transformation. Remote ischemic conditioning (RIC) has demonstrated neuroprotective effects against acute ischemic stroke. However, whether and how RIC regulates rtPA-associated BBB disruption remains unclear. Here, a rodent model of thromboembolic stroke followed by rtPA thrombolysis at different time points was performed with or without RIC. Brain infarction, neurological outcomes, BBB permeability, and intracerebral hemorrhage were assessed. The platelet-derived growth factor CC (PDGF-CC)/PDGFRα pathway in the brain tissue, PDGF-CC levels in the skeletal muscle and peripheral blood were also measured. Furthermore, impact of RIC on serum PDGF-CC levels were measured in healthy subjects and AIS patients. Our results showed that RIC substantially reduced BBB injury, intracerebral hemorrhage, cerebral infarction, and neurological deficits after stroke, even when rtPA was administrated in a delayed therapeutic time window. Mechanistically, RIC significantly decreased PDGFRα activation in ischemic brain tissue and reduced blood PDGF-CC levels, which partially resulted from PDGF-CC reduction in the skeletal muscle of RIC-applied hindlimbs and platelets. Intravenous or intraventricular recombinant PDGF-CC supplementation abolished RIC protective effects on BBB integrity. Moreover, similar changes of PDGF-CC in serum by RIC were also observed in healthy humans and acute ischemic stroke patients. Together, our study demonstrates that RIC can attenuate rtPA-aggravated BBB disruption after ischemic stroke via reducing the PDGF-CC/PDGFRα pathway and thus supports RIC as a potential approach for BBB disruption prevention or treatment following thrombolysis. Graphical Abstract: ga1