NF‐kB p65 Subunit Inhibitor: JSH‐23 Mitigates Diabetic Retinopathy via Reducing Oxidative Stress
Authors: Homme Rubens Petit , Anewesha Laha , Majumder Avisek , George Akash , Singh Mahavir , Tyagi Suresh 
Published: June 2021

Recently we demonstrated that chronic inflammation led to the loss of ocular homeostasis during diabetic retinopathy (DR). However; whether it was propagated via the induction of oxidative stress in the eyes is not known. Oxidative insults can lead to retinal blood vessels damage that in turn may predispose them to leakage of the fluids into the retina along with subsequent development of the retinal hypoxia. These patho‐physiological changes can also result into vision impairment and overtime loss of the vision in DR patients. DR has long been considered as an outcome of neuro degeneration stemming from the excessive inflammation. Studies have pointed out that retinal cells affected by the hyperglycemic environment might exhibit an increase in the levels of oxidative stress markers that are related with NF‐κB activation. We hypothesized that sustained expression of NF‐κB activity leads to an increase in the oxidative stress environment for the retinal capillary and the glial cells in the ocular compartment. These physiological perturbations then induce occlusion and degeneration of the retinal vessels. We set out to investigate the effects of 4‐methyl‐N1 ‐ (3‐phenylpropyl) benzene‐1, 2‐diamine (also referred as JSH‐23); a cell permeable inhibitor for the NF‐κB p65 subunit in a diabetic Akita mouse model. JSH‐23 was injected intraperitoneally; IP @ 5mg/Kg body weight to both Akita and the wild type (WT) mice strains on alternate days for a period of two weeks. Hyperpermeability of retinal vessels and the intraocular pressure (IOP) were assessed via fluorescence angiography and tonometry. Visual functions were measured via the electroretinograms (ERG), and the movement of mice was recorded employing a vision guided behavioral analysis via the light‐dark box test (LDBT). Also, the systemic blood pressure (BP) and the blood glucose levels were monitored using the tail‐cuff coda instrument and glucose meter. The expressions of anti‐oxidative stress enzymes/markers and cellular‐junctional proteins were measured via Western blotting experimentations. The JSH‐23 downregulated total NF‐κB expression levels in retinae but upregulated the expression of SOD1, and catalase to fight excessive oxidative stress in eyes of mice. It also upregulated the junctional proteins: connexin‐43, occludin, and caveolin‐1. Further JSH‐23 downregulated expression of inflammasome marker; such as NLRP3. On the other hand, intervention with JSH‐23 did not change BP however; blood glucose levels were successfully lowered. Additionally, JSH‐23 treatment decreased retinal permeability, and IOP. ERG recording in the light‐adapted settings showed increased amplitude for the A and B‐waves. The vision guided behavior analysis depicted a time decrease for the treated Akita mice. Thus, considering these results we conclude that alleviating oxidative stress via administration of JSH‐23 in the diabetic mice model could improve vision.

Support or Funding Information

HL‐74815, HL‐107640, HL‐139047, AR071789, and NS‐084823

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.