Abstract
Purpose :
Diabetic retinopathy (DR) is a significant cause of blindness, and while treatments for late-stage DR exist, effective interventions for early-stage DR remain lacking. Rapamycin, an FDA-approved drug and a mTOR inhibitor, has emerged as a neuroprotective agent. Our study aimed to investigate the prophylactic neuroprotective effect of long-term, low-dose rapamycin treatment in early-stage DR in Akita mice.
Methods :
Akita mice received intraperitoneal injection of low dose (0.04mg/kg) rapamycin starting 6 weeks before diabetes developed. Retinal function was assessed using ERG at 18, 26, and 36 weeks. Retinal sections were assessed to examine the integrity of retinal neurons such as bipolar cells. Apoptosis was examined via TUNEL assay. Neuroinflammation including microglia activation, and inflammatory mediator expression was assessed by IHC. The expression level of autophagy-related proteins and mTOR activation was assessed using Western blot. Statistical analyses involved one-way ANOVA. Results are presented as mean±SEM (n>5), with significance at P<0.05.
Results :
At 18 weeks old, no reduction in retinal function was observed in Akita mice. However, by 26 weeks old, there was a significant decline in b-wave amplitude in Akita mice (p<0.001). Advancing to 36 weeks old, a substantial decrease in both a-wave (p<0.01) and b-wave (p<0.001) amplitude was observed in Akita mice, highlighting a progressive deterioration in retinal function in DR. In line with this, a notable absence of PKCα expression was observed in the dendrite of bipolar cells adjacent to photoreceptors in Akita mice at 26 weeks and following 36 weeks old. Importantly, rapamycin mitigated the retinal function decrease and maintained retinal structural integrity, as indicated by the elevation of b-wave amplitude (p<0.01) and the presence of PKCα expression (p<0.05) in 26-week-old Akita mice. This neuroprotective effect extended to 36-week-old Akita mice. Additionally, rapamycin suppressed inflammation and reduced apoptosis in the inner nuclear layer, where bipolar cells resided. It also inhibited excessive mTOR activity and regulated disrupted autophagy in Akita mice.
Conclusions :
Prophylactic rapamycin treatment preserved retinal function and structure integrity in Akita mice against retinal neurodegeneration through the suppression of neuroinflammation and the modulation of autophagy in DR.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.