Sensory systemAmelioration of retinal degeneration and proteolysis in acute ocular hypertensive rats by calpain inhibitor ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester
Section snippets
Experimental animals and eyes from human and monkey
Sprague–Dawley rats at 11–12 weeks of age were obtained from Charles River (Yokohama, Japan) and Harlan (Indianapolis, IN, USA). Rhesus monkey (Macaca mulatta) eyes ranging in age from 7 to 15 years were obtained from the Oregon National Primate Research Center (Beaverton, OR, USA) from procedures unrelated to the present studies. Experimental animals were handled in accordance with the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and with the Guiding Principles in
Effect of SNJ-1945 in acute ocular hypertensive rats
H&E staining of retinal sections from rats revealed degeneration after ocular hypertension. The thickness of inner plexiform layer (IPL) and the inner nuclear layer (INL) decreased 7 days after ocular hypertension as compared with sham-operated animals (Fig. 1A). A single i.p. (Fig. 1A) or oral (data not shown) administration of SNJ-1945 helped protect against decreased retinal thickness. The number of cells in GCL was also counted, since glaucoma is associated with the degeneration of RGCs (
Discussion
The major finding of the present study was that a new calpain inhibitor SNJ-1945 with enhanced oral availability ameliorated retinal degeneration in rats suffering from acute ocular hypertension. These are the first data showing that a calpain inhibitor ameliorated retinal degeneration in acute hypertensive rats. The dipeptidyl aldehyde inhibitor SJA6017, N-(4-fluorophenylsulfonyl)-l-valyl-l-leucinal, first showed effectiveness against cataract formation in cultured lenses (Fukiage et al., 1997
Acknowledgments
Dr. Shearer has a significant financial interest (research contract and consulting fee) in Senju Pharmaceutical Co., Ltd. and Dr. Azuma is an employee of Senju Pharmaceutical Co., Ltd., a company that may have a commercial interest in the results of this research and technology. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee was implemented. We thank Noriko Nada for technical assistance.
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2012, Neurobiology of DiseaseCitation Excerpt :It binds and inhibits calpain when calcium levels are high, but releases it when calcium levels fall (Hanna et al., 2007). Recently, an exogenous calpain inhibitor, SNJ-1945, which has shown a strong ability to penetrate the retinal blood barrier after oral administration (Shirasaki et al., 2005), was described to have a neuroprotective effect against retinal cell degeneration in rat and mouse glaucoma models (Oka et al., 2006; Ryu et al., 2011). In this study, we designed our experiment using mice lacking the gene for calpastatin and SNJ-1945 for investigating the role of calpain activation and possibility of neuroprotection under RGC loss induced by hyperglycemia.