Effects of unoprostone on phosphorylated extracellular signal-regulated kinase expression in endothelin-1-induced retinal and optic nerve damage.
Endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been implicated in the development of normal- and high-tension glaucoma. We investigated the effects of unoprostone on extracellular signal-regulated kinase (ERK) in ET-1-induced retinal ganglion cell (RGC) death and optic nerve injury. Our morphometric study showed that intravitreal injection of ET-1 led to cell loss in the RGC layer (RGCL) in 28 days. Western blot analysis showed decreased neurofilament (NF) protein in the optic nerve 28 days after ET-1 injection. In this in vivo model, increased phosphorylated ERK (p-ERK) was observed in the retina on 1 day and subsequently in the optic nerve from 7 days after ET-1 injection. Simultaneous injection of M1, as a metabolite of unoprostone, showed further increased p-ERK levels compared with ET-1 injection alone. Our morphometric study of flat-mount preparations stained with cresyl violet or retrograde labeling with a neuro-tracer and Western blot analysis of NF showed that inhibition of ERK phosphorylation led to acceleration of ET-1-induced RGC death and optic nerve damage. In addition, M1 significantly attenuated both RGC loss and the decrease in NF protein induced by ET-1. The protective effects of M1 were significantly inhibited by U0126, an ERK inhibitor. These results suggest that unoprostone has neuroprotective effects against ET-1-induced neuronal injury through ERK phosphorylation.
Munemasa
Yasunari
Y
Department of Ophthalmology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan.
Kitaoka
Yasushi
Y
Hayashi
Yasuhiro
Y
Takeda
Hiroyuki
H
Fujino
Hiromi
H
Ohtani-Kaneko
Ritsuko
R
Hirata
Kazuaki
K
Ueno
Satoki
S
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D008297:Male; D016900:Neurofilament Proteins / Q000037:antagonists & inhibitors; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009900:Optic Nerve / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology
D019332:Endothelin-1; D016900:Neurofilament Proteins; D018696:Neuroprotective Agents; C051774:neurofilament protein H; C072630:isopropyl unoprostone; D015237:Dinoprost; D048049:Extracellular Signal-Regulated MAP Kinases