Unoprostone reduces oxidative stress- and light-induced retinal cell death, and phagocytotic dysfunction, by activating BK channels.
OBJECTIVE
Unoprostone isopropyl (unoprostone) is a docosanoid currently used as an antiglaucoma agent. Unoprostone is known to have neuroprotective effects and to activate large conductance Ca²⁺-activated K⁺ (BK) channels. Recently, unoprostone has been tested in clinical studies as a therapeutic agent for retinitis pigmentosa (RP) and studies have demonstrated an improvement in retinal sensitivity and in the protection of central retinal sensitivity with its use. However, the mechanism of action underlying unoprostone's protective effect in RP is not fully known. It is well known that the pathogenesis of RP can be accelerated by oxidative stress or light irradiation. Therefore, the current study investigated the effects and the underlying mechanism of action of unoprostone on oxidative stress- and light irradiation-induced damage in photoreceptor and retinal pigment epithelial cultures.


METHODS
The study used the mouse retinal cone-cell line 661W to investigate the effects of unoprostone and its major metabolite, unoprostone-free acid (M1), on oxidative stress- or light irradiation-induced cell death, and a human retinal pigment epithelial cell line (ARPE-19), was used to investigate the effects on light-induced disruption of phagocytotic function in a latex bead assay. Additionally, we examined whether the effects of unoprostone and M1 were mediated by BK channels using iberiotoxin, a selective inhibitor of BK channels.


RESULTS
Unoprostone and M1 protected against light- or H₂O₂-induced cell death in 661W cells, and against light-induced phagocytotic dysfunction in ARPE-19 cells. Additionally, iberiotoxin inhibited the protective effects of unoprostone and M1.


CONCLUSIONS
These findings indicate that unoprostone has protective effects on oxidative stress- and light irradiation-induced damage in vitro and that these effects are mediated by activation of BK channels. This confirms that unoprostone represents a promising therapeutic agent for the treatment of RP and other retinal diseases.
Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan.
Kazuhiro
K
Tsuruma
Yuka
Y
Tanaka
Masamitsu
M
Shimazawa
Yukihiko
Y
Mashima
Hideaki
H
Hara
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008027:Light; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000528:radiation effects; D010455:Peptides / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects / Q000528:radiation effects; D026902:Potassium Channel Blockers / Q000494:pharmacology; D017949:Retinal Cone Photoreceptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects
D000975:Antioxidants; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D026902:Potassium Channel Blockers; C072630:isopropyl unoprostone; C064719:iberiotoxin; D015237:Dinoprost; D006861:Hydrogen Peroxide; D002118:Calcium