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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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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
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
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
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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