{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T02:12:41Z","timestamp":1779934361415,"version":"3.53.1"},"reference-count":61,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council, Australia","doi-asserted-by":"publisher","award":["GNT1700229"],"award-info":[{"award-number":["GNT1700229"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010635","name":"Hunter New England Local Health District","doi-asserted-by":"publisher","award":["GNT2100339"],"award-info":[{"award-number":["GNT2100339"]}],"id":[{"id":"10.13039\/100010635","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001771","name":"University of Newcastle, Australia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001771","id-type":"DOI","asserted-by":"crossref"}]},{"name":"HMRI"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Clopidogrel has been the most commonly used therapy for preventing secondary cardiovascular events since 1997 by inhibiting the purinergic receptor P2Y, G-protein coupled, 12 protein receptor (P2RY12). P2RY12 is critical for microglia function in the brain, where it facilitates repair processes following injury. Under normal conditions, the blood-brain barrier (BBB) prevents peripheral drugs like clopidogrel from entering the brain. However, stroke-induced BBB disruption may allow clopidogrel to interfere with neural recovery by impairing microglia activity. Recently, we demonstrated that clopidogrel worsened cognitive outcomes in young mice after stroke. In this study, we examined the effects of clopidogrel on aged mice, focusing on survival, body weight, neurovascular changes, immune response, and amyloid beta accumulation. Aged male mice underwent photothrombotic stroke (or sham surgery) and received daily clopidogrel or control treatment for 14 days. On day 15, brain tissue was analyzed. Clopidogrel treatment significantly reduced survival and body weight, decreased vessel density, increased vascular permeability, altered microglia activity, and increased amyloid beta levels in the peri-infarct region. Notably, some of these effects were not observed in young mice. These results suggest that BBB disruption in stroke mice enables clopidogrel to enter the central nervous system, where it impairs microglia-mediated restoration of BBB integrity and promotes amyloid accumulation, factors that may contribute to worsened cognitive recovery. This study raises the possibility that clopidogrel may similarly cross the BBB in older stroke patients, impacting microglial function, and emphasizes the need for further research into its mechanisms of action.<\/jats:p>","DOI":"10.3390\/ijms27062547","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T17:04:24Z","timestamp":1773162264000},"page":"2547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Clopidogrel Administration Impairs Neurovascular Unit Recovery and Exacerbates Amyloid Beta Accumulation in Aged Mice Post-Stroke"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8647-9213","authenticated-orcid":false,"given":"Marina","family":"Paul","sequence":"first","affiliation":[{"name":"College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"},{"name":"Centre for Rehab Innovations, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3064-6358","authenticated-orcid":false,"given":"Jonathan W.","family":"Paul","sequence":"additional","affiliation":[{"name":"College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2225-973X","authenticated-orcid":false,"given":"Madeleine","family":"Hinwood","sequence":"additional","affiliation":[{"name":"College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"},{"name":"Centre for Rehab Innovations, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7485-4883","authenticated-orcid":false,"given":"Rebecca J.","family":"Hood","sequence":"additional","affiliation":[{"name":"College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"},{"name":"Discipline of Anatomy and Pathology, School of Biomedicine, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristy","family":"Martin","sequence":"additional","affiliation":[{"name":"College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmoud","family":"Abdolhoseini","sequence":"additional","affiliation":[{"name":"College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"},{"name":"Centre for Rehab Innovations, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8587-0934","authenticated-orcid":false,"given":"Michael","family":"Pollack","sequence":"additional","affiliation":[{"name":"College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"},{"name":"Centre for Rehab Innovations, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Hunter Medical Research Institute, 1 Kookaburra Circuit, New Lambton Heights, NSW 2305, Australia"},{"name":"Centre for Rehab Innovations, University of Newcastle, Callaghan, NSW 2308, Australia"},{"name":"Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, 405 30 Gothenburg, Sweden"},{"name":"Rehabilitation Research Institute of Singapore (RRIS), Nanyang Technological University, Singapore 639798, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frederick 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