CypA inhibition attenuates diabetic hypoglycemia-induced cognitive impairment via the CD147/NF-κB/MMP-9 pathway

Hypoglycemia, a frequent complication of diabetes therapy, induces severe cognitive impairment; however, the underlying mechanisms remain elusive. We aimed to investigate the critical role of the cyclophilin A (CypA)-mediated CD147/nuclear factor-kappa B (NF-κB)/matrix metalloproteinase-9 (MMP-9) inflammatory pathway in hypoglycemia-induced cognitive dysfunction in diabetes and to evaluate the therapeutic potential of CypA inhibition. We employed in vivo diabetic mouse models subjected to hypoglycemia and in vitro human brain vascular pericyte cultures under GD. Quantitative proteomics (tandem mass tag), behavioral assessments (Morris Water Maze), biochemical analyses (western blotting and immunofluorescence), and functional assays (mitochondrial function, migration, and apoptosis) were used to elucidate pathological mechanisms. Cyclosporin A (CsA) was used as a pharmacological cyclophilin inhibitor, and orthogonal pharmacological controls (FK506 and NIM811) were included to assess specificity in vitro. Hypoglycemia induced mitochondrial stress and activated CypA/CD147/NF-κB/MMP-9 signaling, causing pericyte dysfunction, blood-brain barrier (BBB) leakage, neuronal damage, and cognitive deficits in diabetic mice. Pharmacological inhibition of CypA with CsA effectively attenuated these inflammatory signaling changes. CsA treatment ameliorated mitochondrial dysfunction by reducing calcium overload and restoring oxygen consumption rate, decreased pericyte migration and apoptosis, restored BBB integrity, protected neurons, and significantly reversed hypoglycemia-induced cognitive impairment. Proteomic analysis further implicated pericyte and BBB dysfunction in hypoglycemia-induced neural damage. Collectively, our findings identify the CypA-mediated CD147/NF-κB/MMP-9 inflammatory pathway as a key mechanism driving hypoglycemia-induced cognitive dysfunction in diabetes via pericyte injury and BBB disruption. These data support pharmacological cyclophilin/CypA inhibition as a promising strategy for neurovascular protection and cognitive improvement.