Academic Journal
CypA inhibition attenuates diabetic hypoglycemia-induced cognitive impairment via the CD147/NF-κB/MMP-9 pathway.
| Τίτλος: | CypA inhibition attenuates diabetic hypoglycemia-induced cognitive impairment via the CD147/NF-κB/MMP-9 pathway. |
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| Συγγραφείς: | Lin L; 900th Hospital of PLA Joint Logistic Support Force, Fuzhou 350001, China., Huang Z; School of Pharmacy, Fujian Medical University, Fuzhou 350122, China., Huang Q; Fujian Medical University Union Hospital, Fuzhou 350001, China., Huang C; Fujian Medical University Union Hospital, Fuzhou 350001, China., Wu Y; Fujian Medical University Union Hospital, Fuzhou 350001, China., Lin M; Fujian Medical University Union Hospital, Fuzhou 350001, China., Liu L; Fujian Medical University Union Hospital, Fuzhou 350001, China. Electronic address: libinliu@fjmu.edu.cn., Chen Z; School of Pharmacy, Fujian Medical University, Fuzhou 350122, China. Electronic address: chenzhou@fjmu.edu.cn. |
| Πηγή: | Biochemical pharmacology [Biochem Pharmacol] 2026 Jul; Vol. 249, pp. 117917. Date of Electronic Publication: 2026 Mar 21. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE |
| Imprint Name(s): | Publication: Oxford : Elsevier Science Original Publication: Oxford, New York [etc.] Paragamon Press. |
| Ιατρικοί όροι (MeSH): | Matrix Metalloproteinase 9*/metabolism , Cyclophilin A*/antagonists & inhibitors , Cyclophilin A*/metabolism , NF-kappa B*/metabolism , Hypoglycemia*/metabolism , Hypoglycemia*/complications , Hypoglycemia*/drug therapy , Hypoglycemia*/chemically induced , Diabetes Mellitus, Experimental*/metabolism , Diabetes Mellitus, Experimental*/drug therapy , Diabetes Mellitus, Experimental*/complications , Diabetes Mellitus, Experimental*/chemically induced , Basigin*/metabolism , Cognitive Dysfunction*/metabolism , Cognitive Dysfunction*/etiology , Cognitive Dysfunction*/drug therapy , Cognitive Dysfunction*/prevention & control, Signal Transduction/drug effects ; Signal Transduction/physiology ; Cyclosporine/pharmacology ; Cyclosporine/therapeutic use ; Animals ; Male ; Mice ; Humans ; Mice, Inbred C57BL |
| Περίληψη: | 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. (Copyright © 2026 Elsevier Inc. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Contributed Indexing: | Keywords: Blood–brain barrier; Cognitive dysfunction; CypA inhibition; Diabetes; Hypoglycemia |
| Substance Nomenclature: | EC 3.4.24.35 (Matrix Metalloproteinase 9) EC 5.2.1.- (Cyclophilin A) 0 (NF-kappa B) 136894-56-9 (Basigin) 83HN0GTJ6D (Cyclosporine) |
| Entry Date(s): | Date Created: 20260323 Date Completed: 20260713 Latest Revision: 20260713 |
| Update Code: | 20260714 |
| DOI: | 10.1016/j.bcp.2026.117917 |
| PMID: | 41871720 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1873-2968 |
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| DOI: | 10.1016/j.bcp.2026.117917 |