September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Celastrol-mediated survival of retinal ganglion cells is associated with downregulation of TNF-alpha
Author Affiliations & Notes
  • Lei Gu
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Haksu Kyung
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Jacky Man Kwong Kwong
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Daniel Yadegari
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Fei Yu
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Joseph Caprioli
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Natik Piri
    Stein Eye Institute, UCLA, Reseda, California, United States
  • Footnotes
    Commercial Relationships   Lei Gu, None; Haksu Kyung, None; Jacky Man Kwong Kwong, None; Daniel Yadegari, None; Fei Yu, None; Joseph Caprioli, None; Natik Piri, None
  • Footnotes
    Support  This work was supported by The Research to Prevent Blindness (JC) and by the National Institutes of Health (NIH) Grant EY018644 (NP)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 6007. doi:
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      Lei Gu, Haksu Kyung, Jacky Man Kwong Kwong, Daniel Yadegari, Fei Yu, Joseph Caprioli, Natik Piri; Celastrol-mediated survival of retinal ganglion cells is associated with downregulation of TNF-alpha. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6007.

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

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Abstract

Purpose : Celastrol, a triterpenoid isolated from the root extracts of Tripterygium wilfordii (Thunder god vine), has been identified as a neuroprotective agent in various models of neurodegenerative disorders. We have evaluated the effect of celastrol on survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC) and ocular hypertension (OH) and mechanisms underlying its cell protective effect

Methods : ONC and laser trabecular photocoagulation were performed on one eye of adult Brown Norway rats. Animals were treated with intraperitoneal (i.p.; 1 mg/kg) or a single intravitreal (0.2, 1 and 5 mg/kg) injections of celastrol. The extent of RGC degeneration was evaluated by counting RGCs immunolabeled with Rbpms (RNA binding protein with multiple splicing) in a flat-mount retina. Four areas per retinal quadrant (superior, temporal, inferior and nasal) at 1, 2, 3 and 4 mm from the optic disc were analyzed. RGCs were counted in a masked manner

Results : The loss of approximately 23% of RGCs was observed 5 weeks after IOP elevation (Vehicle vs Veh/IOP group; n=10, P=0.0078): 30% in superior, 17% in inferior, 11% in nasal and 35% in temporal regions. Celastrol-treatment increased RGC survival by an average of 24% in the entire retina compared to that in the vehicle-treated group [celastrol/IOP (n=14) vs vehicle/IOP group (n=10), P=0.021]. The average density of RGCs two weeks after ONC in animals treated with daily i.p. injections of vehicle or celastrol was approximately 9.6% and 40.8% of the control group, respectively. This corresponds to approximately a 250% increase in RGC survival mediated by celastrol treatment (n=6 per group; P=0.004). Furthermore, a single intravitreal injection of 1 or 5 mg/kg of celastrol increased the average RGC number in retinas after ONC by approximately 80% compared to vehicle-injected controls (n=4 per group; P<0.05). The expression levels of Hsp70, HO-1 and TNF-alpha in the retina were analyzed to evaluate the roles of these proteins in the celastrol-mediated protection of injured RGCs. Expression of TNF-alpha in retinas of celastrol-treated uninjured and ONC animals was reduced by approximately 2 and 1.5 fold compared to vehicle treated animals, respectively

Conclusions : Celastrol increases cell resistance against OH and ONC-induced injury. The mechanisms underlying celastrol's effect may be associated with modulation of TNF-alpha-mediated cell death

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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