Riluzole inhibits VEGF-induced endothelial cell proliferation in vitro and hyperoxia-induced abnormal vessel formation in vivo.
OBJECTIVE
The present study examined the effects of riluzole, a Food and Drug Administration-approved drug for amyotrophic lateral sclerosis, on VEGF-stimulated endothelial cell proliferation in culture, and on neovascularization in a rat model of retinopathy of prematurity (ROP).


METHODS
Human umbilical vein endothelial cell and bovine retinal endothelial cell cultures were treated with VEGF to induce endothelial cell proliferation in the presence or absence of riluzole. Activation of PKC betaII was examined by quantifying its phosphorylated form on immunoblots. ROP was induced in 5-day-old rat pups by raising them in hyperoxic conditions for 7 days and in normoxic conditions for the next 5 days. Dextran fluorescence retinal angiography was used to quantitatively assess ROP.


RESULTS
Riluzole inhibited VEGF-stimulated PKC betaII activation and cell proliferation in bovine retinal endothelial cell and human umbilical vein endothelial cell cultures. In addition, systemic administration of riluzole substantially ameliorated abnormal new vessel formation in the rat ROP model.


CONCLUSIONS
The present results suggest that riluzole is a potent inhibitor of VEGF-induced endothelial cell proliferation both in vivo and in vitro. Since long-term use of riluzole has already been proven safe in humans, the present data indicate that clinical trials of riluzole for proliferative retinopathies should be implemented expeditiously.
Yoo
Min Heui
MH
Creative Research Initiative Center for the Study of Central Nervous System Zinc and Department of Neurology, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea.
Hyun
Hyae-Jung
HJ
Koh
Jae-Young
JY
Yoon
Young Hee
YH
D000293:Adolescent; D000818:Animals; D000831:Animals, Newborn; D002417:Cattle; D018929:Cell Culture Techniques; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005451:Fluorescein Angiography; D006801:Humans; D018496:Hyperoxia / Q000150:complications; D007231:Infant, Newborn; D011247:Pregnancy; D011493:Protein Kinase C / Q000378:metabolism; D064546:Protein Kinase C beta; D051381:Rats; D017207:Rats, Sprague-Dawley; D015861:Retinal Neovascularization / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D012171:Retinal Vessels / Q000166:cytology; D012178:Retinopathy of Prematurity / Q000201:enzymology / Q000209:etiology / Q000517:prevention & control*; D019782:Riluzole / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000633:toxicity
D018691:Excitatory Amino Acid Antagonists; D042461:Vascular Endothelial Growth Factor A; D019782:Riluzole; D011493:Protein Kinase C; D064546:Protein Kinase C beta