Caspase-3 inhibitor transiently delays inherited retinal degeneration in C3H mice carrying the rd gene.
BACKGROUND
The effect of a caspase-3 inhibitor on retinal degeneration in C3H mice carrying the rd gene, a mutation of a rod-specific phosphodiesterase, was investigated.


METHODS
A quantity of 2 mg/kg of Ac-DEVD-CHO, as inhibitor, was injected intraperitoneally every other day from 8 days of age, and retinal damage was compared with that in saline-treated C3H mice at 13 days (1 day after the third treatment) and 17 days of age (1 day after the fifth treatment). Retina of ICR mice not carrying rd gene was also evaluated under the same protocol. The efficacy of Ac-DEVD-CHO was evaluated based on total retinal thickness and outer retinal thickness (thickness of outer nuclear layer and photoreceptor layer). An apoptotic index and a cell proliferation index for the photoreceptor cells, at 13 days of age, were calculated based on terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick-end labeling (TUNEL) and proliferating cell nuclear antigen (PCNA) labeling, respectively.


RESULTS
At 13 days of age, total and outer retinal thickness in saline-treated C3H mice were 140.3 microm and 37.5 microm, compared with 160.4 microm and 49.5 microm, respectively, in Ac-DEVD-CHO-treated C3H mice ( P<0.01, respectively). In ICR mice, total and outer retinal thickness were 182.1 microm and 90.9 microm, respectively, in saline-treated mice and 183.8 microm and 89.6 microm in Ac-DEVD-CHO-treated mice (not significant). At this time, the TUNEL index was 23.52 cells/10(4) microm (2) of outer nuclear layer in saline-treated C3H mice; Ac-DEVD-CHO treatment significantly reduced this value to 18.73 cells/10(4) microm(2) ( P<0.05). The TUNEL index in saline- and Ac-DEVD-CHO-treated ICR mice was 0.59 cells/10(4) microm(2) and 0.80 cells/10(4) microm(2), respectively (not significant); Ac-DEVD-CHO treatment had no influence on normally developing retina. The PCNA index was not affected by Ac-DEVD-CHO-treatment. However, at 17 days of age, Ac-DEVD-CHO treatment did not ameliorate retinal degeneration.


CONCLUSIONS
The caspase-3 inhibitor was transiently effective in delaying retinal degeneration through inhibition of the apoptosis of photoreceptor cells in rd gene-carrying mice. The use of caspase-3 inhibitors may have therapeutic applications in the treatment of human retinal degeneration.
Yoshizawa
Katsuhiko
K
Department of Pathology II, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan.
Kiuchi
Katsuji
K
Nambu
Hiroyuki
H
Yang
Jihong
J
Senzaki
Hideto
H
Kiyozuka
Yasuhiko
Y
Shikata
Nobuaki
N
Tsubura
Airo
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3; D061945:Caspase Inhibitors; D002455:Cell Division / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D005260:Female; D020287:In Situ Nick-End Labeling; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008813:Mice, Inbred ICR; D009687:Nuclear Proteins / Q000235:genetics*; D009842:Oligopeptides / Q000494:pharmacology*; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects* / Q000473:pathology; D016601:RNA-Binding Proteins; D012162:Retinal Degeneration / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D009687:Nuclear Proteins; D009842:Oligopeptides; D016601:RNA-Binding Proteins; C498268:Rdbp protein, mouse; C099158:acetyl-aspartyl-glutamyl-valyl-aspartal; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3