Retinal Inflammation, Oxidative Stress, and Vascular Impairment Is Ablated in Diabetic Mice Receiving XMD8-92 Treatment

Abstract

The global number of diabetics continues to rise annually. As diabetes progresses, almost all of Type I and more than half of Type II diabetics develop diabetic retinopathy. Diabetic retinopathy is a microvascular disease of the retina, and is the leading cause of blindness in the working-age population worldwide. With such a significant health impact, new drugs are required to halt the blinding threat posed by this visual disorder. The cause of diabetic retinopathy is multifactorial, and an optimal therapeutic would halt inflammation, cease photoreceptor cell dysfunction, and ablate vascular impairment. XMD8-92 is a small molecule inhibitor that blocks inflammatory activity downstream of ERK5 (extracellular signal-related kinase 5) and BRD4 (bromodomain 4). ERK5 elicits inflammation, is increased in Type II diabetics, and plays a pathologic role in diabetic nephropathy, while BRD4 induces retinal inflammation and plays a role in retinal degeneration. Further, we provide evidence that suggests both pERK5 and BRD4 expression are increased in the retinas of our STZ (streptozotocin)-induced diabetic mice. Taken together, we hypothesized that XMD8-92 would be a good therapeutic candidate for diabetic retinopathy, and tested XMD8-92 in a murine model of diabetic retinopathy. In the current study, we developed an in vivo treatment regimen by administering one 100 μL subcutaneous injection of saline containing 20 μM of XMD8-92 weekly, to STZ-induced diabetic mice. XMD8-92 treatments significantly decreased diabetes-mediated retinal inflammation, VEGF production, and oxidative stress. Further, XMD8-92 halted the degradation of ZO-1 (zonula occludens-1), which is a tight junction protein associated with vascular permeability in the retina. Finally, XMD8-92 treatment ablated diabetes-mediated vascular leakage and capillary degeneration, which are the clinical hallmarks of non-proliferative diabetic retinopathy. Taken together, this study provides strong evidence that XMD8-92 could be a potentially novel therapeutic for diabetic retinopathy.

Adiponectin Ameliorates Hyperglycemia-Induced Retinal Endothelial Dysfunction, Highlighting Pathways, Regulators, and Networks

“…A previous study in diabetic mice showed that BRD4 induces retinal inflammation and plays a role in retinal degeneration. 48 Adiponectin downregulates BRD4 kinase activity, which could suppress the inflammatory process and angiogenesis functions.…”

Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

“…111 Additionally, while there is evidence of increased MAP kinase signaling in ALS patients as well as in animal and iPSC models, 57,[112][113][114][115] two compounds identified here were MAP kinase inhibitors (XMD-892, XMD-885). Finally, XMD-892 116 and other compounds (tacedinaline, [117][118][119] MLN4924, 120 piperlongumine, 121,122 prunetin 123 ) have also been under investigation for their antioxidant, anti-inflammatory, anti-ischemic, neuroprotective, and/or antitumour properties.…”

Anti-IL17A Halts the Onset of Diabetic Retinopathy in Type I and II Diabetic Mice

“…Acellular capillaries were quantified in the retinal vasculature as previously described [ 18 , 19 , 20 , 21 ]. Eyes were fixed with 10% formalin.…”

“…After IL-17A binds to IL-17R, Act1-TRAF (TNF receptor associated factor) signaling cascades then activate NF-κB-dependent inflammation, FADD-dependent endothelial cell death, and ERK5-dependent oxidative stress in the diabetic retina. This leads to retinal vascular impairment and the onset of non-proliferative diabetic retinopathy [ 18 , 19 , 20 , 21 ].…”