Calpain inhibitor protects cells against light-induced retinal degeneration.
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.
Imai
Shunsuke
S
Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Shimazawa
Masamitsu
M
Nakanishi
Tomohiro
T
Tsuruma
Kazuhiro
K
Hara
Hideaki
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002219:Carbamates / Q000494:pharmacology / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D004596:Electroretinography; D008027:Light / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010770:Phosphotransferases / Q000378:metabolism; D010786:Photoreceptor Cells / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology / Q000528:radiation effects; D012162:Retinal Degeneration / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D013049:Spectrin / Q000378:metabolism
C515164:((1S)-1-((((1S)-1-benzyl-3-cyclopropylamino-2,3-di-oxopropyl)amino)carbonyl)-3-methylbutyl)carbamic acid 5-methoxy-3-oxapentyl ester; D002219:Carbamates; C492236:Cdk5r1 protein, mouse; D013049:Spectrin; D010770:Phosphotransferases; D002154:Calpain; C505524:Casp7 protein, mouse; D053148:Caspase 3; D053179:Caspase 7