Abstract
Purpose :
To evaluate the neuroprotective effect of a HECT domain-E3 ubiquitin ligase inhibitor, M01, on retinal ganglion cells after ischemic injury.
Methods :
AION induction was achieved using laser-coupled photoactivation of the optic disc after intravenously injecting Rose Bengal through the tail vein. The male Wistar rats were divided into three experimental groups: (1) sham, (2) AION induction and subcutaneously (SC) injected with PBS, and (3) AION induction and SC injected with M01 (100 mg/kg in 0.2 ml PBS) for 3 consecutive days. Animals were sacrificed at 28 days post-infarct. Evaluation methods include the TUENL assay and retrograde labeling of fluorogold (FG) in retinal ganglion cells (RGCs) and immunohistochemical studies of ED1 in optic nerves (ON). Western blot analysis was performed for pro-surviving signaling. Visual function was evaluated by flash visual evoked potential (FVEP).
Results :
Administration of M01 (100 mg/kg) significantly increased RGC survival and preserved visual function after AION induction. The number of TUNEL-positive cells and ED1-positive cells was significantly decreased, and optic disc edema was reduced considerably after ischemic infarction with M01 treatment. Moreover, M01 effectively ameliorated optic nerve demyelination and enhanced M2 microglial polarization after AION induction. M01 enhanced the expression of nuclear factor erythroid 2-related factor (Nrf2); subsequently, it downregulated thioredoxin interacting protein (TXNIP) expression, inhibited NLR family pyrin domain containing 3 (NLRP3) activation, and further decreased inflammatory factors, interleukin (IL)-1b and IL-6, in the retina after ischemic injury.
Conclusions :
These findings suggest that M01 may have therapeutic potential in treating ischemic optic neuropathy and other ischemic damage-related diseases by modulating Nrf2 and TXNIP/NLRP3 inflammasome pathways within the retina and optic nerve.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.