Neuroprotective effects of the protein kinase inhibitors, SBJ-051 and sunitinib in light-induced photoreceptor cell death

Abstract

Purpose : Several kinase pathways have identified as an important modulator on retinal cell survival and functional integrity. Based on our previous finding on multi-kinase inhibitor, sunitinib-mediated RGC protection, we tested potential protective effects of sunitinib and more potent inhibitor, SBJ-051 on photoreceptor (PR) degeneration in the murine light-damage model.

Methods : Female BALB/cJ mice (12wk) were administered with SBJ-051 (10 and 60 mg/kg), sunitinib (15, 30 and 60 mg/kg), or vehicle (5% DMSO) by daily intraperitoneal injection starting 72 h prior to LD up to 6 days post LD. Mice were dark-adapted and insulted with ~3000 lux cool fluorescent light for 4 h followed by immediate dark recovery. Serial SD-OCT imaging, immunohistochemistry, and scotopic ERG were used to assess retinal structure and function. The LD-associated gene expression was profiled using RT-PCR analysis. Phosphorylation of JNK and c-Jun was also assessed from post LD retinas.

Results : Vehicle-treated animals showed a significant decrease (44.78 ± 0.03%, P<0.001) in the retinal outer layer thickness (ROL: OPL to PR) in response to LD. This was also associated with a significant decrease in ERG a-wave (89.99 ± 4.99%, P<0.01) and b-wave (75.61 ± 6.94%, P<0.01) amplitudes. Administration of SBJ-051 at 10 mg/kg and sunitinib at 60 mg/kg markedly attenuated LD-induced ROL thinning up to the latest time point tested. The effect of LD on the ERG a-wave and b-wave amplitudes was also significantly improved with both 10 mg/kg SBJ-051 (a-wave: 67.44 ± 11.93%, b-wave: 58.7 ± 17.65%; P<0.05) and 60 mg/kg sunitinib (a-wave: 62.23 ± 9.54%, b-wave: 65.11 ± 13.43%; P<0.05). Both compounds reduced the loss of rhodopsin and cone arrestin expression with also decreased 5-hydroxy-methyl-cytosine positive cells in the outer nuclear layer. The upregulation of c-jun, c-fos, osmr, mt2 and ho1 gene expression at 0 and 3 hours after LD was significantly reduced by 10 mg/kg SBJ-051. SBJ-051 administration also attenuated LD-induced upregulation of retinal JNK and c-Jun phosphorylation (3 h).

Conclusions : Our data demonstrates that SBJ-051 (10 mg/kg) and sunitinib (60 mg/kg) promote PR survival and function following PR damage by LD. We are currently defining the molecular target(s) and mechanisms that mediate the PR neuroprotective activity of these compounds with various approaches.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.