May 2006
Volume 47, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2006
Reduction of Photoreceptor Cell Death by Calpain Inhibitor SNJ–1945 in N–Methyl–N–Nitrosourea Treated Rats
Author Affiliations & Notes
  • T. Oka
    Kobe Creative Center, Senju Pharmaceutical Co Ltd, Kobe, Japan
  • T. Nakajima
    Kobe Creative Center, Senju Pharmaceutical Co Ltd, Kobe, Japan
  • T.R. Shearer
    Department of Integrative Biosciences, Oregon Health & Science University, Portland, OR
  • M. Azuma
    Kobe Creative Center, Senju Pharmaceutical Co Ltd, Kobe, Japan
    Department of Integrative Biosciences, Oregon Health & Science University, Portland, OR
  • Footnotes
    Commercial Relationships  T. Oka, Senju Pharmaceutical, E; T. Nakajima, Senju Pharmaceutical, E; T.R. Shearer, Senju Pharmaceutical, C; M. Azuma, Senju Pharmaceutical, E.
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science May 2006, Vol.47, 4802. doi:
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      T. Oka, T. Nakajima, T.R. Shearer, M. Azuma; Reduction of Photoreceptor Cell Death by Calpain Inhibitor SNJ–1945 in N–Methyl–N–Nitrosourea Treated Rats . Invest. Ophthalmol. Vis. Sci. 2006;47(13):4802.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : Photoreceptor cell death induced by the DNA–alkylating agent N–methyl–N–nitrosourea (MNU) is relevant to retinitis pigmentosa. We previously reported involvement of the protease calpain in photoreceptor cell death in rats treated with MNU. Calpain inhibitor SNJ–1945 was recently synthesized and can be administered orally. The purpose of the present experiments was to determine if calpain inhibitor SNJ–1945 reduced photoreceptor cell death induced by MNU in rats.

Methods: : Photoreceptor cell death was induced by a single intraperitoneal injection of MNU (60 mg/kg body weight) to Sprague–Dawley rats. Just after MNU injection, calpain inhibitor SNJ–1945 was administered orally as a single dose of 200 mg/kg body weight and thereafter once daily. Photoreceptor cell death was evaluated in histological sections of retinas stained by H&E and by TUNEL staining. Activation of calpain isoforms and proteolysis of calpain substrates were analyzed by casein zymography and immunoblotting.

Results: : TUNEL–positive nuclei in outer nuclear layer were observed 1 day after MNU injection. Severe loss of photoreceptor cells was observed 7 days after MNU injection. Calpain inhibitor SNJ–1945 significantly reduced photoreceptor cell death induced by MNU in rats. Several presumptive biochemical indicators of calpain activation accompanied the morphologic changes.

Conclusions: : Our results showed that orally administered calpain inhibitor SNJ–1945 reduced photoreceptor cell death induced by MNU in rats. If future studies show that calpain is involved in photoreceptor cell death in humans, inhibition of calpain could be tested in optimal drug therapy against conditions showing photoreceptor cell death, such as retinitis pigmentosa.

Keywords: proteolysis • calcium • pathology: experimental 
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