Celastrol, a quinine methide triterpene extracted from the perennial vine Tripterygium wilfordii (Celastraceae), has been used in traditional Chinese medicine as a natural remedy for inflammation and a variety of autoimmune diseases for hundreds of years. Celastrol has been identified as a potential neuroprotective candidate in a comprehensive drug screen against various neurodegenerative diseases and has since been demonstrated to have cell protective properties in animal models of “protein misfolding” neurodegenerative disorders such as Parkinson’s, Hungtington’s, Alzheimer’s diseases, and amyotrophic lateral sclerosis. The neuroprotective effects of celastrol are associated with the activation of heat shock and antioxidant responses that lead to an induction of an array of cytoprotective genes involved in protein folding/aggregation/turnover and the scavenging and export of reactive species. Furthermore, celastrol was shown to attenuate microglial activation and production of tumor necrosis factor (TNF)-alpha. Since protein misfolding/aggregation, oxidative damage and microglial activation have been associated with the pathogenesis of glaucoma, we hypothesized that celastrol could be a potent multifactorial therapeutic drug for the treatment of this disease.
The degeneration of retinal ganglion cells (RGCs) and their axons in the optic nerve is the cause of visual impairment in patients with optic neuropathies, including glaucoma, which affects more than 65 million people worldwide and is a leading cause of irreversible blinding. Chronic forms of the glaucoma usually progress over many years. Currently, reduction of intraocular pressure (IOP) remains the main strategy in slowing the progression of the disease. Yet, glaucomatous neuropathy often continues to progress even after IOP has been reduced, especially in advanced stages of disease. It is clear that it is necessary to develop new strategies to supplement or perhaps even to replace IOP reduction in some patients in order to reduce the number of degenerating neurons and preserve the surviving RGCs and their axons. However, this is extremely difficult since the exact molecular pathways of RGC death in glaucoma are not well understood, and the cellular damage in this disease maybe caused by different molecular mechanisms that have the common characteristics of optic nerve damage and visual loss patterns. Since the pathophysiologic mechanisms underlying RGC loss in glaucoma remain unclear, several directions of RGC neuroprotection are being investigated, including blocking glutamate excitotoxicity, stabilizing Ca2+ homeostasis, inhibiting nitric oxide production, overexpressing proteins regulating the cellular redox state, supplying neurotrophins, preventing apoptosis, inducing heat shock response, and modulating the immunologic status. Each of these strategies increases the rate of RGC survival in the laboratory setting. However, their effect is limited due to the possible presence of diverse mechanisms involved in glaucomatous RGC degeneration, and none of these strategies have been evaluated clinically with the exception of memantine (NMDA receptor antagonist) trials which showed no significant beneficial effect compared to placebo.
The effect of intraperitoneal injection of celastrol on RGC survival damaged by ONC
ONC was performed unilateraly with the contralateral eye remaining untreated. Celastrol (1mg/kg) or vehicle (DMSO) was injected i.p. daily starting on the day of ONC and continued for 14 days, after which retinas were dissected and analyzed to determine the number of surviving RGCs. The dose of celastrol was chosen based on previous studies in in vivo model systems utilizing this drug. The number of surviving cells was determined by counting RGCs immunolabeled with Rbpms in flat-mount retinal preparations. Rbpms has characterized as a marker of RGCs in rodent retinas with a specificity matching that of retrograde labeling. An extensive loss of RGCs (~87% RGC loss in DMSO-treated group) was observed in retinas subjected to ONC. The extent of RGC loss was similar across the superior, inferior and temporal quadrants that were sampled in this experiment. The average density of remaining RGCs in retinas of celastrol-treated animals was approximately 1332152 cells/mm2, or 46% of that of the Celastrol/Control, whereas for the Vehicle/ONC group it was about 381758 RGCs/mm2, or 12.5% of Vehicle/Control (n=6 per group; *P=0.004). These data indicate a more than 250% increase in RGC survival mediated by celastrol treatment compared to the Vehicle/ONC control group.
Reference:
Haksu Kyung, BRAIN RESEARCH 1609 (2015) 21-30