title: 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 (1mg/kg) was approximately 1332 cells/mm(2), or 40.8% of the Celastrol/Control group. In retinas of the Vehicle/ONC group about 381 RGCs/mm(2) 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 Vehicle/ONC group. Furthermore, the average RGC number in retinas of ONC animals treated with a single intravitreal injection of 1mg/kg or 5mg/kg of celastrol was increased by approximately 80% (760 RGCs/mm(2)) and 78% (753 RGCs/mm(2)), respectively, compared to Vehicle/ONC controls (422 cells/mm(2)). Injection of 0.2mg/kg of celastrol had no significant effect on cell survival, with the average number of RGCs being 514 cells/mm(2) in celastrol-treated animals versus 422 cells/mm(2) 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 suggest that mechanisms underlying celastrol׳s RGC protective effect are associated with inhibition of TNF-alpha-mediated cell death.
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA; National Medical Center, Seoul, Republic of Korea.
authors: Haksu
authors: H
authors: Kyung
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors: Jacky M K
authors: JM
authors: Kwong
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors: Vlad
authors: V
authors: Bekerman
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors: Lei
authors: L
authors: Gu
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors: Daniel
authors: D
authors: Yadegari
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA.
authors: Joseph
authors: J
authors: Caprioli
authors: Jules Stein Eye Institute, University of California Los Angeles, Los Angeles, CA, USA; Brain Research Institute, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: piri@jsei.ucla.edu.
authors: Natik
authors: N
authors: Piri
mesh_terms: D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000378:metabolism; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D009409:Nerve Crush; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053978:Pentacyclic Triterpenes; D051381:Rats; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018840:HSP70 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C000619709:Hsf1 protein, rat; C568775:Hsf2 protein, rat; D018696:Neuroprotective Agents; D053978:Pentacyclic Triterpenes; D014157:Transcription Factors; D014315:Triterpenes; D014409:Tumor Necrosis Factor-alpha; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; C050414:celastrol
keywords: Celastrol; Ganglion cells; Neuroprotection; Optic nerve; Retina