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 lightinduced 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 ␣-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 ␣-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.

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“…ERG measurements in mice were performed as described in our previous report [50]. Electroretinograms (ERGs) were recorded 5 days after light exposure (Mayo, Aichi, Japan).…”

Ligation of the Pterygopalatine and External Carotid Arteries Induces Ischemic Damage in the Murine Retina

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Hyperactivation of retina by light in mice leads to photoreceptor cell death mediated by VEGF and retinal pigment epithelium permeability

“…Indeed, several studies have shown that exposure to high-intensity of light induces photoreceptor loss (light-damage model or LD) by several mechanisms that can be specific to the LD model 13 and by some other mechanisms that are common to other inherited retinal dystrophies. 14, 15 Interestingly, different studies showed that after LD the retina presents some cardinal features of AMD. 16, 17, 18, 19 For instance, LD leads to the accumulation of reactive oxygen species and generation of toxic metabolites such as N-retinylidene-N-retinylethanolamine (A2E), partially degraded proteins and lipid–protein adducts.…”