Abstract
Purpose: :
Celastrol has been demonstrated to have neuroprotective properties in animal models of Parkinson's, Hungtington's, Alzheimer's diseases and amyotrophic lateral sclerosis. The cell protective effects of celastrol are associated with its ability to activate two major cell stress pathways: heat shock and antioxidant responses. The aim of this study was to evaluate the neuroprotective effect of celastrol in a rat model of retinal ganglion cell (RGC) degeneration induced by optic nerve crush (ONC).
Methods: :
ONC was performed on one eye of twenty two adult Brown Norway rats weighing 240-294g. Daily intraperitoneal injections of Celastrol (1mg/kg) or vehicle were administered for two weeks. To evaluate the extent of RGC degeneration at 14 days after ONC, the number of surviving cells were determined by counting RGCs immunolabeled with Rbpms (RNA binding protein with multiple splicing) in a flat-mount retinal preparations. The retina was divided into superior, inferior and temporal quadrants and three sampling fields (0.32 mm x 0.24 mm) were collected at each region of 1, 2, and 3 mm from the center of the optic nerve in each retinal quadrant. The numbers of RGCs in 27 sampling fields from each retina were counted and averaged. RGC loss in this study was evaluated in four groups of animals: Celastrol/No-ONC (n=6), Vehicle/No-ONC (n=5), Celastrol/ONC (n=5) and Vehicle/ONC (n=6).
Results: :
The effect of the Celastrol administration on cell survival was evaluated 14 days after ONC, which leads to a rapid and specific degeneration of RGCs. Celastrol/No-ONC group (221 ± 32.7 / magnification x 200) showed an approximately 15.6% decrease in RGC numbers compared to Vehicle/No-ONC group (261 ± 28.3, p = 0.006). In the Vehicle/ONC group (25.1 ± 7.4) RGCs loss was 90.4% whereas in the Celastrol/ONC group (90.3 ± 17.2) 59.2% of the cells degenerated (p = 0.004). Results of this study indicate that Celastrol administration protects 30% of RGCs from ONC induced degeneration.
Conclusions: :
Cell protective effect of Celastrol observed in ONC model provides optimism for testing this potent multifactorial therapeutic drug to preserve RGCs in animal models of optic neuropathies such as glaucoma, pathogenesis of which is associated with protein misfolding/aggregation and oxidative damage.
Keywords: neuroprotection • ganglion cells • immunohistochemistry