RT Journal Article
SR Electronic
T1 A Novel Calpain Inhibitor, ((1<em>S</em>)-1-((((1<em>S</em>)-1-Benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic Acid 5-Methoxy-3-oxapentyl Ester (SNJ-1945), Reduces Murine Retinal Cell Death In Vitro and In Vivo
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 380
OP 387
DO 10.1124/jpet.109.156612
VO 332
IS 2
A1 Masamitsu Shimazawa
A1 Shinsuke Suemori
A1 Yuta Inokuchi
A1 Nozomu Matsunaga
A1 Yoshimi Nakajima
A1 Takayuki Oka
A1 Tetsuya Yamamoto
A1 Hideaki Hara
YR 2010
UL http://jpet.aspetjournals.org/content/332/2/380.abstract
AB We examined whether ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester (SNJ-1945), a new orally available calpain inhibitor, might reduce retinal cell death in vivo and/or in vitro. Retinal cell damage was induced in vivo in mice by intravitreal injection of N-methyl-d-aspartate (NMDA), and SNJ-1945 was intraperitoneally or orally administered twice. NMDA-induced calpain activity (measured as the cleaved products of α-spectrin) and its substrate, p35 (a neuron-specific activator for cyclin-dependent kinase 5), in the retina were examined by immunoblotting. In RGC-5 (a rat retinal ganglion cell line) cell culture, cell damage was induced by a 4-h oxygen-glucose deprivation (OGD) treatment followed by an 18-h reoxygenation period. In mouse retinas, SNJ-1945 (30 or 100 mg/kg i.p., 100 or 200 mg/kg p.o.) significantly inhibited the cell loss in the ganglion cell layer (GCL) and the thinning of the inner plexiform layer induced by NMDA. Furthermore, the number of positive cells for terminal deoxynucleotidyl transferase dUTP nick-end labeling was significantly reduced in the GCL and the inner nuclear layer of retinas treated with SNJ-1945 compared with vehicle-treated retinas 24 h after NMDA injection. Levels of cleaved α-spectrin products increased and p35 decreased 6 h after NMDA injection or later, and their effects were attenuated by SNJ-1945. In vitro, SNJ-1945 (10 and 100 μM) inhibited the OGD stress-induced reduction in cell viability. In conclusion, SNJ-1945 may afford valuable neuroprotection against retinal diseases, because it was effective against retinal damage both in vitro and in vivo. Our results also indicate that calpain activation and subsequent p35 degradation may be involved in the mechanisms underlying retinal cell death. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics