Celastrol supports survival of retinal ganglion cells injured by optic nerve crush

Abstract

The present study evaluates the effect of celastrol on the survival of retinal ganglion cells (RGCs) injured by optic nerve crush (ONC). Celastrol, a quinine methide triterpene extracted from the perennial vine Tripterygium wilfordii (Celastraceae), has been identified as a potential neuroprotective candidate in a comprehensive drug screen against various neurodegenerative diseases. Two weeks after ONC, the average density of remaining RGCs in retinas of animals treated with daily intraperitoneal (i.p.) injections of celastrol (1 mg/kg) was approximately 1332 cells/mm2, or 40.8% of that of the Celastrol/Control group. In retinas of the Vehicle/ONC group about 381 RGCs/mm2 were counted, which is 9.6% of the total number of RGCs in the DMSO/Control group. This corresponds to approximately a 250% increase in RGC survival mediated by celastrol treatment compared to control. Furthermore, the average RGC number in retinas of ONC animals treated with a single intravitreal injection of 1 mg/kg or 5 mg/kg of celastrol was increased by approximately 80% (760 RGCs/ mm2) and 78% (753 RGCs/mm2), respectively, compared to controls (422 cells/mm2). Injection of 0.2 mg/kg of celastrol had no significant effect on cell survival compared to DMSO-injected controls, with the average number of RGCs being 514 cells/mm2 in celastrol-treated animals versus 422 cells/mm2 in controls. The expression levels of Hsp70, Hsf1, Hsf2, 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. No statistically significant change in HO-1, Hsf1 and Hsp70 levels was seen in animals with ONC. An approximately 2 fold increase in Hsf2 level was observed in celastrol-treated animals with or without injury. Hsf2 level was also increased 1.8 fold in DMSO-treated animals with ONC injury compared to DMSO-treated animals with no injury suggesting that Hsf2 induction has an injury-induced component. 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. The observed results point to the role of TNF-alpha in RGC degeneration following axonal injury, and that suggests mechanisms underlying celastrol’s RGC protective effect is associated with inhibition of TNF-alpha-mediated cell death.

The effect of celastrol on the ocular hypertension-induced degeneration of retinal ganglion cells

“…The regimen for celastrol treatment in experiments with the ONC model was based on earlier published studies on successful use of celastrol in rat and mouse models of various human diseases with no side effects [21–23]. However, we observed an approximately 2% body weight loss in the celastrol-injected animals, whereas animals in the control group injected with DMSO only registered a weight gain of 6% during a two-week period [19]. Consistent with our findings, the body weight decrease of animals treated with celastrol was also observed during i.p.…”

“…Recently, we analyzed the effect of celastrol on the survival of RGCs injured by ONC [19]. Both intraperitoneal (i.p.)…”

A role of Heat Shock Protein 70 in Photoreceptor Cell Death: Potential as a Novel Therapeutic Target in Retinal Degeneration

“…Therefore, protection of photoreceptor cells may be a useful therapeutic strategy for RDs. Some of the candidate therapeutic agents for RDs are listed in Table []; these agents include therapeutic agents against the early stage of photoreceptor cell death (antioxidants, ROS scavengers, Ca 2+ antagonists and calpain inhibitors), therapeutic agents against the late stage of photoreceptor cell death (cathepsin inhibitors and caspase inhibitors), and HSP70 inducers.…”

“…In addition to these existing therapies, we further propose that HSP70 inducers could be novel therapeutic agents to prevent photoreceptor cell death in RDs. Many different chemicals have been reported as HSP70 inducers, including arimoclomol , celastrol , eupalinolide A/B , paeoniflorin , and radicicol (Table ). Drug repositioning is the process of developing new indications for existing drugs or biologics.…”

Pharmacological induction of Heat Shock Protein 70 by celastrol protects motoneurons from excitotoxicity in rat spinal cord in vitro

“…Celastrol has been tested as a neuroprotectant in various models of neurodegeneration with a beneficial outcome (Deane & Brown, ; Faust et al., ; Gu et al., ; Jantas et al., ; Kyung et al., ; Sun et al., ; Xu et al., ; Zhang et al., ) by inducing rapid HSP70 expression (Allison et al., ; Cascão, Fonseca, & Moita, ; Chow & Brown, ; DeMeester, Buchman, & Cobb, ; Kannaiyan, Shanmugam, & Sethi, ; Salminen et al., ; Traynor et al., ; Trott et al., ; Welsh, Moyer, & Harris, ; Westerheide et al., ). Its action on spinal excitotoxicity remains, however, to be studied.…”