June 2023
Volume 64, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2023
Long-term Administration with Low Dose Rapamycin Improves Retinal Function in a Mouse Model of Early Diabetic Retinopathy
Author Affiliations & Notes
  • Yipin Wang
    Ophthalmology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Ka Cheung Tam
    Ophthalmology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Tsz Chung Ng
    Ophthalmology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Wei Wang
    Ophthalmology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Wai Ching Lam
    Ophthalmology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
    Ophthalmology, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada
  • Amy CY Lo
    Ophthalmology, The University of Hong Kong Li Ka Shing Faculty of Medicine, Hong Kong, Hong Kong
  • Footnotes
    Commercial Relationships   Yipin Wang None; Ka Cheung Tam None; Tsz Chung Ng None; Wei Wang None; Wai Ching Lam None; Amy Lo None
  • Footnotes
    Support  General Research Fund, Research Grants Council, The Government of the Hong Kong Special Administrative Region (17112919)
Investigative Ophthalmology & Visual Science June 2023, Vol.64, 1005. doi:
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      Yipin Wang, Ka Cheung Tam, Tsz Chung Ng, Wei Wang, Wai Ching Lam, Amy CY Lo; Long-term Administration with Low Dose Rapamycin Improves Retinal Function in a Mouse Model of Early Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2023;64(8):1005.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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