Abstract
Purpose :
Rapamycin, a specific inhibitor of mTOR (mechanistic target of rapamycin) and an FDA-approved drug, has been implemented in over 10 clinical trials for the treatment of ocular neurodegenerative diseases including diabetic retinopathy (DR). However, the mechanism of mTOR inhibitor for treating DR has not been fully elucidated. In this study, we sought to investigate the crosstalk of mTOR-mediated autophagy and neurodegeneration events in DR and identify the neuroprotective roles of rapamycin in early DR in Ins2Akita mice.
Methods :
Ins2Akita and wildtype mice received intraperitoneal injections of low dose (0.04mg/kg) rapamycin every other day beginning 6 weeks after the onset of diabetes till 26 weeks of age; Flash electroretinogram was recorded to examine the retinal function (n = 9 mice per strain); Retinal histologic sections followed by H&E staining or immunofluorescence (IF) were conducted to evaluate the morphological alteration, neuroinflammation, apoptotic death, autophagy, and the activation of mTOR, and the presence of apoptosis was confirmed by TUNEL assay; Statistical comparisons among multiple groups were performed by one-way analysis of variance (ANOVA) followed by posthoc Tukey’s multiple comparison tests. The mean ± standard error of the mean (SEM) was presented. P<0.05 was considered statistically significant.
Results :
Rapamycin improved retinal function in 26 weeks age old Ins2Akita mice by alleviating b-wave amplitude (p<0.0001). Rapamycin also preserved the retinal structure by alleviating the inner nuclear layer (INL) (p<0.05) and the inner plexiform layer (INL) (p<0.05) reduction and maintained the synaptic connectivity between rod-bipolar cells and rod photoreceptors in Ins2Akita mice (p<0.05). Microglia activation and the expression of inflammatory mediators were suppressed after rapamycin administration in Ins2Akita mice (p<0.01). The modulation of neuroinflammation by rapamycin ameliorated the apoptosis in the ganglion cell layer (GCL) and INL. Finally, we found rapamycin inhibited mTOR activity and modulated autophagy in Ins2Akita mice.
Conclusions :
Long-term, low-dose rapamycin administration preserved retinal function and retinal structure in Ins2Akita mice against retinal neurodegeneration through the suppression of neuroinflammation and the modulation of autophagy in DR.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.