September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-κB Axis during Retinal Inflammation
Author Affiliations & Notes
  • Tomohiro Okamoto
    Ophthalmology, Keio University School of Medicine, Shinjuku, Japan
    Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Japan
  • Mamoru Kamoshita
    Ophthalmology, Keio University School of Medicine, Shinjuku, Japan
    Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Japan
  • Hideto Osada
    Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Japan
  • Eriko Toda
    Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Japan
  • Norihiro Nagai
    Ophthalmology, Keio University School of Medicine, Shinjuku, Japan
    Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Japan
  • Kazuo Tsubota
    Ophthalmology, Keio University School of Medicine, Shinjuku, Japan
  • Yoko Ozawa
    Ophthalmology, Keio University School of Medicine, Shinjuku, Japan
    Laboratory of Retinal Cell Biology, Keio University School of Medicine, Shinjuku, Japan
  • Footnotes
    Commercial Relationships   Tomohiro Okamoto, None; Mamoru Kamoshita, None; Hideto Osada, None; Eriko Toda, None; Norihiro Nagai, None; Kazuo Tsubota, None; Yoko Ozawa, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 579. doi:
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      Tomohiro Okamoto, Mamoru Kamoshita, Hideto Osada, Eriko Toda, Norihiro Nagai, Kazuo Tsubota, Yoko Ozawa; The Neuroprotective Effect of Rapamycin as a Modulator of the mTOR-NF-κB Axis during Retinal Inflammation. Invest. Ophthalmol. Vis. Sci. 2016;57(12):579.

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

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Abstract

Purpose : The determination of the molecular mechanism underlying retinal pathogenesis and visual dysfunction during innate inflammation, and the treatment effect of rapamycin thereon.

Methods : The endotoxin-induced uveitis and retinitis mouse model was established by injecting lipopolysaccharide. The mice were subsequently treated with rapamycin, a mammalian target of rapamycin (mTor) inhibitor. The rhodopsin mRNA and protein expression level in the retina, and photoreceptor outer segment (OS) length was measured, and visual function was recorded by electroretinography. Inflammatory cytokines, their related molecules, mTor, and LC3 levels were measured by real-time PCR and/or immunoblotting. Leukocyte adhesion during inflammation was analyzed using concanavalin A lectin.

Results : The post-transcriptional reduction in the visual pigment of rod photoreceptor cells, rhodopsin, OS length, and rod photoreceptor cell dysfunction during inflammation were suppressed by rapamycin. Activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induction of inflammatory cytokines, such as interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the activation of the downstream signaling protein, signal transducer and activator of transcription 3 (STAT3), which reduces rhodopsin in the retina during inflammation, were attenuated by rapamycin. Increased leukocyte adhesion was attenuated by rapamycin. Interestingly, although mTor activation was observed after NF-κB activation, mTor inhibition suppressed NF-κB activation at the early phase, indicating that the basal level of activated mTor was sufficient to activate NF-κB in the retina. In addition, the inhibition of NF-κB suppressed mTor activation, suggesting a positive feedback loop of mTOR and NF-κB during inflammation. The ratio of LC3II to LC3I was not changed by inflammation, but increased by rapamycin.

Conclusions : Our results propose the potential use of rapamycin as a neuroprotective therapy to suppress local activated mTor levels, related inflammatory molecules, and the subsequent visual dysfunction during retinal inflammation.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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