AUTHOR=Lendvai-Emmert Dominika , Magyar-Sumegi Zsofia Dina , Hegedus Emoke , Szarka Nikolett , Fazekas Balint , Amrein Krisztina , Czeiter Endre , Buki Andras , Ungvari Zoltan , Toth Peter 

TITLE=Mild traumatic brain injury-induced persistent blood–brain barrier disruption is prevented by cyclosporine A treatment in hypertension

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1252796

DOI=10.3389/fneur.2023.1252796

ISSN=1664-2295

ABSTRACT=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) -matrixmetalloproteinase-9 (MMP-9) pathway in cerebral vessels leading to BBB disruption. 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. 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. 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.