Abstract
Diabetic retinopathy (DR) is one of the most common complications of Diabetes Mellitus (DM) and is directly associated with inflammatory processes. Currently, neuro-inflammation is considered an early event in DR and proceeds via microglia polarization. A hallmark of DR is the presence of retinal reactive gliosis. Here we report the beneficial effect of (S S,1R)-1-docecylsulfiny-5N,6O-oxomethylidenenojirimycin ((Ss)-DS-ONJ), a member of the sp2-iminosugar glycolipid (sp2-IGL) family, by decreasing iNOS and inflammasome activation in Bv.2 microglial cells exposed to pro-inflammatory stimuli. Moreover, pretreatment with (Ss)-DS-ONJ increased Heme-oxygenase (HO)-1 as well as interleukin 10 (IL10) expression in LPS-stimulated microglial cells, thereby promoting M2 (anti-inflammatory) response by the induction of Arginase-1. The results strongly suggest that this is the likely molecular mechanism involved in the anti-inflammatory effects of (S S)-DS-ONJ in microglia. (S S)-DS-ONJ further reduced gliosis in retinal explants from type 1 diabetic BB rats, which is consistent with the enhanced M2 response. In conclusion, targeting microglia polarization dynamics in M2 status by compounds with anti-inflammatory activities offers promising therapeutic interventions at early stages of DR.
Highlights
Most patients with diabetes mellitus (DM) will develop some grade of diabetic retinopathy (DR) [1]
As a proof of concept, we have studied the effect of (SS,1R)-1dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (referred to as (SS)-DS-ONJ, Figure 1) in Bv.2 microglial cells and retinal explants of type 1 diabetic BB rats within the environment of inflammation and immune modulation associated with Diabetic retinopathy (DR)
Bv.2 microglial cells were cultured for 24 h in the presence or absence of LPS (200 ng/mL) plus (SS)-DS-ONJ (1 or 10 mM) or M2 cytokines (IL4/IL13) in the pre-treatment regimen
Summary
Most patients with diabetes mellitus (DM) will develop some grade of diabetic retinopathy (DR) [1]. The incidence of DR is growing and will increase several fold in the coming decades. It is the main cause of visual failure in the working-age population [2]. DR is consider a common microvascular complication of DM, and it generally involves microvascular complications of capillary endothelium and pericytes. A M2-Response Induction Delay DR Progression leading to micro-aneurysm, blood retinal barrier (BRB) leakage and fragile new blood vessel formation (neovascularization) [3]. Retinal neurodegeneration is present before to clinically-overt microvascular disturbances, and recent evidences suggest that neurodegeneration collaborates on the development of microvascular dysfunction and neovascularization [4]. Several agents with neuroprotective actions are, being studied as potential therapeutics against DR [5]
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