Abstract
Mitochondrial μ-calpain and apoptosis-inducing factor (AIF)-dependent photoreceptor cell death has been seen in several rat and mouse models of retinitis pigmentosa (RP). Previously, we demonstrated that the specific peptide inhibitor of mitochondrial μ-calpain, Tat-µCL, protected against retinal degeneration following intravitreal injection or topical eye-drop application in Mertk gene-mutated Royal College of Surgeons rats, one of the animal models of RP. Because of the high rate of rhodopsin mutations in RP patients, the present study was performed to confirm the protective effects of Tat-µCL against retinal degeneration in rhodopsin transgenic S334ter and P23H rats. We examined the effects of intravitreal injection or topical application of the peptide on retinal degeneration in S334ter and P23H rats by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay, electroretinogram (ERG), immunohistochemistry for AIF, and histological staining. In S334ter rats, we found that intravitreal injection or topical application of the peptide prevented photoreceptor cell death from postnatal (PN) 15 to 18 days, the time of early-stage retinal degeneration. Topical application of the peptide also delayed attenuation of ERG responses from PN 28 to 56 days. In P23H rats, topical application of the peptide protected against photoreceptor cell death and nuclear translocation of AIF on PN 30, 40, and 50 days, as the primary stages of degeneration. We observed that topical application of the peptide inhibited the thinning of the outer nuclear layer and delayed ERG attenuations from PN 30 to 90 days. Our results demonstrate that the mitochondrial μ-calpain and AIF pathway is involved in early-stage retinal degeneration in rhodopsin transgenic S334ter and P23H rats, and inhibition of this pathway shows curative potential for rhodopsin mutation-caused RP.
Highlights
Retinitis pigmentosa (RP) is a hereditary retinal degeneration characterized by night blindness, photophobia, gradual loss of the peripheral visual field, color blindness, and eventual visual disturbance
Results showed that the number of TUNELpositive cells in the outer nuclear layer (ONL) was decreased with intravitreal injection of Tat-mCL (,50% inhibition) and PD150606 (,33% inhibition)
We have previously shown that mitochondrial calpains are activated and truncate apoptosis-inducing factor (AIF), followed by the release of truncated AIF from the mitochondria into the nucleus in the initial stage of retinal degeneration in Royal College of Surgeons (RCS) rats [6]
Summary
Retinitis pigmentosa (RP) is a hereditary retinal degeneration characterized by night blindness, photophobia, gradual loss of the peripheral visual field, color blindness, and eventual visual disturbance. Despite the numerous gene mutations, RP occurs in association with rod photoreceptor apoptosis as a common pathway [1] This apoptosis has been detected in animal models of RP such as retinal degeneration 1 (rd1), retinal degeneration slow (rds), and rhodopsin (Rho) mutant mice [2]. Recent studies have revealed that calpains and/or AIF cause photoreceptor cell death in Royal College of Surgeons (RCS), Rho S334ter, and Rho P23H rats, and rd, rd10, and Rho T17 M mice [3,4,6,7,8,9,10] These results are supported by many reports showing that intracellular concentrations of calcium ions are elevated during photoreceptor degeneration in the rat and mouse models of RP [1]
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