Calpain inhibitor protects cells against light-induced retinal degeneration.

Abstract

Calpains are activated by excessive light exposure and related to retinal degeneration. We investigated the protective effects of ((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 calpain inhibitor, against light-induced retinal degeneration in mice. SNJ-1945 was orally administrated at doses of 100 and 200 mg/kg at 30 min before and just after light exposure. Light-induced calpain activation was evaluated by using proteolysis of α-spectrin and p35 (a neuron-specific activator for cyclin-dependent kinase 5). The effects of SNJ-1945 against light-induced retinal damage were examined by the thickness of the outer nuclear layer (ONL). Photoreceptor apoptosis was assessed by counting terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells in ONL. Retinal functions were measured in terms of a- and b-wave amplitudes by using an electroretinogram. As the mechanism of SNJ-1945, caspase-3/7 measurement was carried out. SNJ-1945 inhibited the proteolysis of α-spectrin and p35 by light exposure and presented a decrease in the numbers of TUNEL-positive cells and ONL atrophy. Furthermore, SNJ-1945 presented a decrease in a- and b-wave amplitude and caspase-3/7 activation induced by light exposure. These findings suggest that the activation of calpain plays a pivotal role in photoreceptor degeneration by light exposure, and SNJ-1945 may be a candidate for effectively treating diseases related to photoreceptor degeneration.

• Authors: Shunsuke Imai, Masamitsu Shimazawa, Tomohiro Nakanishi, Kazuhiro Tsuruma, Hideaki Hara
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 335 Issue 3 Pg. 645-52 (Dec 2010) ISSN: 1521-0103 [Electronic] United States
• PMID: 20823194 (Publication Type: Journal Article)

Chemical References

• ((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester
• Carbamates
• Cdk5r1 protein, mouse
• Spectrin
• Phosphotransferases
• Calpain
• Casp7 protein, mouse
• Caspase 3
• Caspase 7

Topics

• Animals
• Apoptosis (drug effects, radiation effects)
• Calpain (antagonists & inhibitors, metabolism)
• Carbamates (pharmacology, therapeutic use)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Electroretinography
• Light (adverse effects)
• Male
• Mice
• Mice, Inbred Strains
• Phosphotransferases (metabolism)
• Photoreceptor Cells (drug effects, pathology, radiation effects)
• Retina (drug effects, metabolism, physiopathology, radiation effects)
• Retinal Degeneration (etiology, pathology, physiopathology, prevention & control)
• Spectrin (metabolism)