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Maki Kuro, Katsuhiko Yoshizawa, Norihisa Uehara, Clark Y. Lai, Sayaka Kanematsu, Hisanori Miki, Ayako Kimura, Takashi Yuri, Kanji Takahashi, Airo Tsubura; Calpain Inhibition Restores Basal Autophagy And Suppresses Apoptosis On MNU-induced Photoreceptor Cell Injury In Mice. Invest. Ophthalmol. Vis. Sci. 2011;52(14):4352.
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A single systemic administration of N-methyl-N-nitrosourea (MNU) causes retinal degeneration involving photoreceptor cell death within 7 days. MNU-induced photoreceptor cell death is due to apoptosis and is a reliable animal model for human retinitis pigmentosa. The purpose of this study was to elucidate the involvement of calpain-mediated autophagy as well as apoptosis on the cell death cascade caused by MNU, and to evaluate the efficacy of calpain inhibitor SNJ-1945.
Seven-week-old female BALB/c mice were left untreated or received an intraperitoneal (ip) injection of MNU, and MNU-exposed mice were treated with ip injection of SNJ-1945 or with vehicle (distilled water containing 0.5% carboxymethyl cellulose) 3 hr prior to MNU and thereafter once daily until sacrifice. Eyes were examined histologically, histochemically, and morphometrically analyzed photoreceptor cell ratio and retinal damage ratio. Extracted retinal proteins were examined for the expression of caspase-3, microtubule-associated protein light chain 3 (LC3), autophagy protein 5 (Atg5), and α-spectrin by Western blot analysis.
During 3 days after MNU exposure, compared with the MNU-untreated control retina, caspase-3 expression increased, LC3 expression decreased, and Atg5 expression decreased 24 hr after MNU exposure, indicating increased apoptosis and decreased autophagy levels. MNU-induced photoreceptor cell death was caused by increased calpain activation as measured by α-spectrin proteolysis products, while SNJ-1945 ameliorated photoreceptor cell death through blocking calpain activation and by restoring basal autophagy.
Calpain activation is involved in MNU-induced photoreceptor cell death and calpain inhibition effectively restored photoreceptor cell autophagy, suppressed apoptosis, and rescued photoreceptor cell death in mice.
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