Abstract

Retinal diabetic neuropathy (RDN) precedes retinal microvascular pathology in diabetic retinopathy (DR), but the therapy by antagonizing RDN to stall DR is rare. Emerging evidence including ours suggest that serine racemase (SRR) drives DR at least by promoting RDN. Thus, we explore the therapy by antagonizing SRR to stall and treat DR. We herein indicate that inhibition of SRR by oral gavage of l-aspartic acid {beta}-hydroxymate (L-ABH), a competitive inhibitor of SRR, mitigated photoreceptor dysfunction, loss of retinal ganglion cells (RGC) and retinal endothelial cell and pericyte in db/db mice, a type II diabetes model. To dissect the mechanism, intravitreal injection of L-ABH mitigates glutamate-induced neurotoxicity in the retina. In the whole body, gastrointestinal-based delivery of L-ABH maintained euglycemia and improved glucose tolerance either in db/db mice or in diet-induced obesity mice. In conclusion, inhibition of SRR prevented retinal neurovascular abnormalities in diabetic animals through executing neuroprotection in the retina and maintaining glucose homeostasis in the system. Our study reveals a novel strategy to prevent DR.