Introduction
Orexins, hypothalamic neuropeptides, play a critical role in promoting wakefulness. Suvorexant, a dual orexin receptor antagonist, which is primarily indicated for the treatment of insomnia, also lowers blood glucose. Similarly, in rodent studies, suvorexant has shown beneficial effects on overall glucose homeostasis. Using an animal model of type 2 diabetes (T2D) db/db mice, we hypothesized that suvorexant treatment could improve the ocular complications of T2D.
Reseach design and methods
Male db/db mice were treated daily with suvorexant (30 mg/kg, intraperitoneal) or vehicle at Zeitgeber time 0–2 for 12 weeks. The following visual assessments were performed to study the effects of suvorexant: electroretinogram, optomotor response test, and fluorescein angiography. Glucose and insulin tolerance tests were performed to assess the impact on glycemic control. After euthanasia, retinas were isolated, and qPCR and immunofluorescence staining were performed.
Results
Suvorexant treatment improved visual acuity and vascular parameters, including reduced avascular and increased vascular areas. There was a decrease in scotopic a-wave and b-wave amplitudes in suvorexant-treated mice, along with increased b-wave implicit time. Suvorexant downregulated mRNA of phospholipase C 1 and protein kinase C beta, as well as inflammatory markers tumor necrosis factor-α (Tnf-a) and interleukin 1β (Il-1b). Consistent with changes in mRNA levels, suvorexant reduced protein expression of PKCβ and CD45 in immunofluorescence studies of retinal transverse sections. Furthermore, suvorexant-treated mice demonstrated improved glucose tolerance compared with vehicle-treated mice.
Conclusions
We found that suvorexant improved visual acuity and retinal vascular insufficiency by reducing retinal inflammation and improving glucose homeostasis in db/db mice. Our findings suggest that orexin receptor inhibition, with suvorexant, may be a potential treatment for ocular complications associated with T2D.
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