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

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

doi:10.3389/fneur.2023.1252796

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

Front Neurol. 2023 Nov 20:14:1252796. doi: 10.3389/fneur.2023.1252796. eCollection 2023.

Authors

Dominika Lendvai-Emmert^{1

2}, Zsofia Dina Magyar-Sumegi^{1

2}, Emoke Hegedus^{1

2

3}, Nikolett Szarka⁴, Balint Fazekas^{1

2}, Krisztina Amrein^{1

2

5}, Endre Czeiter^{1

2

5}, Andras Buki^{1

6}, Zoltan Ungvari^{7

8}, Peter Toth^{1

2

5

7

8}

Affiliations

¹ Department of Neurosurgery, Medical School, University of Pecs, Pecs, Hungary.
² Neurotrauma Research Group, Szentagothai Research Centre, University of Pecs, Pecs, Hungary.
³ Department of Anaesthesiology and Intensive Therapy, Medical School, University of Pecs, Pecs, Hungary.
⁴ Department of Primary Health Care, Medical School, University of Pecs, Pecs, Hungary.
⁵ ELKH-PTE Clinical Neuroscience MR Research Group, University of Pecs, Pecs, Hungary.
⁶ Department of Neurosurgery, Faculty of Medicine and Health, Orebro University, Orebro, Sweden.
⁷ Department of Neurosurgery, Vascular Cognitive Impairment and Neurodegeneration Program, Oklahoma Center for Geroscience and Healthy Brain Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States.
⁸ Department of Public Health, International Training Program in Geroscience, Doctoral School of Basic and Translational Medicine, Semmelweis University, Budapest, Hungary.

Abstract

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.

Keywords: BBB; CyPA; hypertension; mTBI; neuroinflammation.

Abstract

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