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Mild traumatic brain injury-induced persistent blood-brain barrier disruption is prevented by cyclosporine A treatment in hypertension
Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary; Neurotrauma Research Group, Szentagothai Research Centre, University of Pecs, Pecs, Hungary.
Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary; Neurotrauma Research Group, Szentagothai Research Centre, University of Pecs, Pecs, Hungary.
Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary; Neurotrauma Research Group, Szentagothai Research Centre, University of Pecs, Pecs, Hungary; Department of Anaesthesiology and Intensive Therapy, Medical School, University of Pecs, Pecs, Hungary.
Department of Primary Health Care, Medical School, University of Pecs, Pecs, Hungary.
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2023 (English)In: Frontiers in Neurology, E-ISSN 1664-2295, Vol. 14, article id 1252796Article in journal (Refereed) Published
Abstract [en]

INTRODUCTION: Mild traumatic brain injury (mTBI) and hypertension synergize to induce persistent disruption of the blood-brain barrier (BBB), neuroinflammation and cognitive decline. However, the underlying mechanisms are not known. Cerebral production of Cyclophilin A (CyPA) is induced in hypertension and after TBI, and it was demonstrated to activate the nuclear factor-κB (NF-kB)- matrix-metalloproteinase-9 (MMP-9) pathway in cerebral vessels leading to BBB disruption.

METHODS: To test the role of CyPA in mTBI- and hypertension-induced BBB disruption we induced mTBI in normotensive and spontaneously hypertensive rats (SHR), then the animals were treated with cyclosporine A (a specific inhibitor of CyPA production) or vehicle for 7 days. We assessed BBB permeability and integrity, cerebral expression and activity of the CyPA-NF-kB-MMP-9 pathway, extravasation of fibrin and neuroinflammation.

RESULTS: We found that mild TBI induced BBB disruption and upregulation of the CyPA-NF-kB-MMP-9 pathway in hypertension, which were prevented by blocking CyPA. Cyclosporine treatment and preservation of BBB function prevented accumulation of blood-derived fibrin in the brain parenchyma of hypertensive rats after mTBI and reversed increased neuroinflammation.

DISCUSSION: We propose that mTBI and hypertension interact to promote BBB disruption via the CyPA-NF-kB-MMP-9 pathway, and inhibition of cyclophilin production after mTBI may exert neuroprotection and improve cognitive function in hypertensive patients.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023. Vol. 14, article id 1252796
Keywords [en]
BBB, CyPA, hypertension, mTBI, neuroinflammation
National Category
Neurosciences
Identifiers
URN: urn:nbn:se:oru:diva-110375DOI: 10.3389/fneur.2023.1252796ISI: 001114016900001PubMedID: 38073626Scopus ID: 2-s2.0-85178954957OAI: oai:DiVA.org:oru-110375DiVA, id: diva2:1820472
Note

Funding Agencies:

National Research, Development and Innovation Office OTKA K-134555 OTKA FK-123798

Hungarian Academy of Sciences Bolyai Research Scholarship

National Clinical Neuroscience Laboratory RRF-2.3.1-21-2022-00011

Thematic Excellence Program 2021 Health sub-program of the Ministry for Innovation and Technology in Hungary, within the framework of the EGA-16 project of the University of Pecs

National Institute on Aging RF1AG072295 R01AG055395 R01AG068295 K01-AG073614

National Institute of Neurological Disorders and Stroke R01NS100782

National Cancer Institute R01CA255840

Available from: 2023-12-18 Created: 2023-12-18 Last updated: 2024-09-04Bibliographically approved

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