The sp 2 -iminosugar glycolipid 1-dodecylsulfonyl-5 N ,6 O -oxomethylidenenojirimycin (DSO 2 -ONJ) as selective anti-inflammatory agent by modulation of hemeoxygenase-1 in Bv.2 microglial cells and retinal explants

Abstract

Neuroinflammation is an early event during diabetic retinopathy (DR) that impacts the dynamics of microglia polarization. Gliosis is a hallmark of DR and we have reported the beneficial effects of 1R-DSO-ONJ, a member of the sp-iminosugar glycolipid (sp-IGL) family, in targeting microglia and reducing gliosis in diabetic db/db mice. Herein, we analyzed the effect of DSO-ONJ, another family compound incorporating a sulfone group that better mimics the phosphate group of phosphatidylinositol ether lipid analogues (PIAs), in Bv.2 microglial cells treated with bacterial lipopolysaccaride (LPS) and in retinal explants from db/db mice. In addition to decreasing iNOS and inflammasome activation, the anti-inflammatory effect of DSO-ONJ was mediated by direct p38α MAPK activation. Computational docking experiments demonstrated that DSO-ONJ binds to p38α MAPK at the same site where PIAs and the alkyl phospholipid perifosine activators do, suggesting similar mechanism of action. Moreover, treatment of microglial cells with DSO-ONJ increased both heme-oxygenase (HO)-1 and Il10 expression regardless the presence of LPS. In retinal explants from db/db mice, DSO-ONJ also induced HO-1 and reduced gliosis. Since IL-10-mediated induction of HO-1 expression is mediated by p38α MAPK activation, our results suggest that this molecular mechanism is involved in the anti-inflammatory effects of DSO-ONJ in microglia.

BHDPC Is a Novel Neuroprotectant That Provides Anti-neuroinflammatory and Neuroprotective Effects by Inactivating NF-κB and Activating PKA/CREB

“…Microglia-mediated neuroinflammation is characterized by pro-inflammatory molecule production, these molecules are neurotoxic and subsequently result in death and damage of neighboring neurons ( Chan et al, 2017 ; Chen et al, 2017 ; Alcalde-Estevez et al, 2018 ). Therefore, agents that are able to block pro-inflammatory mediators would be expected to confer neuroprotection.…”

Probing the Inhibitor versus Chaperone Properties of sp2-Iminosugars towards Human β-Glucocerebrosidase: A Picomolar Chaperone for Gaucher Disease

“…The glycosidase inhibitory and chaperoning abilities of sp 2 -iminosugars have been found to be strongly dependent on the mono- [ 32 , 33 , 34 , 35 , 36 ] or bicyclic structure of the sugar glycone-like skeleton [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ], the configurational pattern [ 45 , 46 , 47 , 48 ], and the nature of nonglycone-type substituents [ 49 , 50 , 51 ]. Differently from classical iminosugars, for which the lability of aminal functionalities prevents the installation of anomeric substituents (except in the case of pseudo- C -glycosides) [ 52 , 53 , 54 , 55 ], sp 2 -iminosugars can bear O -, S -, N -, or C -anomeric aglycone groups while keeping full chemical and configurational stability [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 ], even when multivalently presented [ 66 , 67 , 68 , 69 ]. The possibility of accessing reducing analogues with a precise α-like axial orientation of the anomeric hydroxyl is quite unique [ 70 , 71 , 72 ].…”

Effect of Topical Administration of Somatostatin on Retinal Inflammation and Neurodegeneration in an Experimental Model of Diabetes

“…The anti-inflammatory properties of the compound DSO2-ONJ, a member of the sp2-iminosugar glycolipid (sp2-IGL) family, have recently been reported [ 26 ]. This effect is mediated by direct p38α MAPK activation in microglial cells.…”

“…Of relevance is the direct activation of p38α MAPK by SST in Bv.2 microglial cells in a similar way reported by others with phosphatidylinositol ether lipid analogs (PIAs) and the alkyl phospholipid perifosine that displayed anti-inflammatory properties [ 43 , 44 ]. In the same line, our recent study with DSO2-ONJ, a member of the sp2-iminosugar glycolipid (sp2-IGL) family, showed that it was able to decrease inflammation in microglial cells and retinal explants through molecular mechanisms associated to the activation of p38α MAPK [ 26 ]. Therefore, further studies are necessary to decipher similarities in the mechanism of action between SST and these lipid-related compounds.…”