title: Critical role of calpain in axonal damage-induced retinal ganglion cell death.
abstract: Calpain, an intracellular cysteine protease, has been widely reported to be involved in neuronal cell death. The purpose of this study is to investigate the role of calpain activation in axonal damage-induced retinal ganglion cell (RGC) death. Twelve-week-old male calpstatin (an endogenous calpain inhibitor) knockout mice (CAST KO) and wild-type (WT) mice were used in this study. Axonal damage was induced by optic nerve crush (NC) or tubulin destruction induced by leaving a gelatin sponge soaked with vinblastine (VB), a microtubule disassembly chemical, around the optic nerve. Calpain activation was assessed by immunoblot analysis, which indirectly quantified the cleaved α-fodrin, a substrate of calpain. RGCs were retrogradely labeled by injecting a fluorescent tracer, Fluoro-Gold (FG), and the retinas were harvested and flat-mounted retinas prepared. The densities of FG-labeled RGCs harvested from the WT and CAST KO groups were assessed and compared. Additionally, a calpain inhibitor (SNJ-1945, 100 mg/kg/day) was administered orally, and the density of surviving RGCs was compared with that of the vehicle control group. The mean density of surviving RGCs in the CAST KO group was significantly lower than that observed in the WT group, both in NC and in VB. The mean density of surviving RGCs in the SNJ-1945-treated group was significantly higher than that of the control group. The calpain inhibitor SNJ-1945 has a neuroprotective effect against axonal damage-induced RGC death. This pathway may be an important therapeutic target for preventing this axonal damage-induced RGC death, including glaucoma and diabetic optic neuropathy and other CNS diseases that share a common etiology.
authors: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors: Morin
authors: M
authors: Ryu
authors: Masayuki
authors: M
authors: Yasuda
authors: Dong
authors: D
authors: Shi
authors: Ahmed Y
authors: AY
authors: Shanab
authors: Ryo
authors: R
authors: Watanabe
authors: Noriko
authors: N
authors: Himori
authors: Kazuko
authors: K
authors: Omodaka
authors: Yu
authors: Y
authors: Yokoyama
authors: Jiro
authors: J
authors: Takano
authors: Takaomi
authors: T
authors: Saido
authors: Toru
authors: T
authors: Nakazawa
mesh_terms: D000596:Amino Acids; D000818:Animals; D001369:Axons / Q000473:pathology*; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000172:deficiency; D002154:Calpain / Q000378:metabolism*; D002219:Carbamates / Q000627:therapeutic use; D002352:Carrier Proteins / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000473:pathology*; D012160:Retina / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D013266:Stilbamidines; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism; D013049:Spectrin
chemical_list: D000596:Amino Acids; D019208:Brain-Derived Neurotrophic Factor; D002135:Calcium-Binding Proteins; D002154:Calpain; D002219:Carbamates; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D008840:Microfilament Proteins; D016900:Neurofilament Proteins; D013266:Stilbamidines; D014404:Tubulin; D013049:Spectrin; C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; C462941:beta3 tubulin, mouse; C098463:dolaisoleucine; C033668:calpastatin