The benzodiazepine anesthetic midazolam prevents hyperglycemia‐induced microvascular leakage in the retinas of diabetic mice

Abstract

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, generation of reactive oxygen species (ROS), and transglutaminase activation in HRECs; these effects were reversed by the GABA, type A (GABA) 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 activation, 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 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.

n-3 Fatty Acid and Its Metabolite 18-HEPE Ameliorate Retinal Neuronal Cell Dysfunction by Enhancing Müller BDNF in Diabetic Retinopathy

“…Supplementation with VEGF may also have affected the ROS production; there was no increase in the extracellular concentration of H 2 O 2 from HRECs in the medium without VEGF, even with 25 mmol/L glucose. VEGF can promote the production of ROS by HRECs (59). Nevertheless, we considered it reasonable to use supplementation with VEGF to mimic the intraocular condition of retinal damage from diabetes.…”

Dopamine ameliorates hyperglycemic memory-induced vascular dysfunction in diabetic retinopathy

“…VEGF, a vascular permeability factor, plays a key role in DR (Lee et al, 2016). Previously, it was reported that VEGF activates transglutaminase 2 (TGase2) by intracellular Ca 2+ elevation and ROS generation and subsequently induces microvascular leakage through adherens junction disassembly in the retinas of diabetic mice (Lee et al, 2017; Lee et al, 2018). We found that VEGF levels were persistently elevated in the retinas of HGM mice and that dopamine prevented vascular leakage induced by intradermal injection of VEGF into mouse ears.…”

The vicious cycle between transglutaminase 2 and reactive oxygen species in hyperglycemic memory–induced endothelial dysfunction

“…CP also prevents hyperglycemia‐induced vascular leakage and metastasis of melanoma cells by inhibiting TGase2 in the lungs of diabetic mice (30). TGase2 plays an essential role in hyperglycemia‐induced vascular leakage in the retinas of diabetic mice (24), which was prevented by CP, the benzodiazepine anesthetic midazolam, or cysteamine derived from coenzyme A degradation (27, 36, 37). In the present study, oral administration of Cys inhibited hyperglycemia‐induced TGase2 activation and ROS generation in the aortas of HGM mice.…”

“…In situ TGase transamidating activity was determined by confocal microscopy, as previously described in Lee et al . (27). Briefly, cells were incubated with 1 mM 5‐(biotinamido)pentylamine at 37° for 1 h and then fixed and permeabilized.…”