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The benzodiazepine anesthetic midazolam prevents hyperglycemia‐induced microvascular leakage in the retinas of diabetic mice
Author(s) -
Lee Yeon-Ju,
Kim Minsoo,
Lee Jee-Yeon,
Jung Se-Hui,
Jeon Hye-Yoon,
Lee Seung Ah,
Kang Seongsik,
Han Eun-Taek,
Park Won Sun,
Hong Seok-Ho,
Kim Young-Myeong,
Ha Kwon-Soo
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201800014rr
Subject(s) - flumazenil , midazolam , gabaa receptor , benzodiazepine , pharmacology , evans blue , endocrinology , chemistry , receptor , medicine , sedation
We investigated the beneficial effects of midazolam against vascular endothelial growth factor (VEGF)‐induced vascular leakage and its molecular mechanism of action in human retinal endothelial cells (HRECs) and the retinas of diabetic mice. Midazolam inhibited VEGF‐induced elevation of intracellular Ca 2+ , generation of reactive oxygen species (ROS), and transglutaminase activation in HRECs; these effects were reversed by the GABA, type A (GABA A ) receptor antagonist flumazenil but not by the translocator protein antagonist PK11195. Midazolam also prevented VEGF‐induced disassembly of adherens junctions and in vitro permeability. Intravitreal injection of midazolam prevented hyperglycemia‐induced ROS generation, transglutaminase activa tion, and subsequent vascular leakage in the retinas of diabetic mice, and those effects were reversed by flumazenil. The roles of flumazenil were further supported by identifying GABA A receptors in mouse retinas. Thus, midazolam prevents hyperglycemia‐induced vascular leakage by inhibiting VEGF‐induced intracellular events in the retinas of diabetic mice.—Lee, Y.‐J., Kim, M., Lee, J.‐Y., Jung, S.‐H., Jeon, H.‐Y., Lee, S. A., Kang, S., Han, E.‐T., Park, W. S., Hong, S.‐H., Kim, Y.‐M., Ha, K.‐S. The benzodiazepine anesthetic midazolam prevents hyperglycemia‐induced microvascular leakage in the retinas of diabetic mice. FASEB J. 32, 6089–6099 (2018). www.fasebj.org