Neuroprotective effects of beta-secretase inhibitors against rat retinal ganglion cell death.
Beta-secretase, an enzyme participating in amyloid beta-peptide generation, is thought to be involved in the pathogenesis of Alzheimer's disease. We examined the effects of beta-secretase inhibitors such as N-benzyloxycarbonyl-Val-Leu-leucinal (Z-VLL-CHO) and H-EVNstatineVAEF-NH2 (GL-189) on glutamate-induced retinal ganglion cell (RGC) death in vitro. In cultures of purified RGCs from neonatal rats, 2-day exposure to 25 microM glutamate induced RGC death, and Z-VLL-CHO (100 nM) and GL-189 (1 microM) had neuroprotective effects. We also found out that Z-VLL-CHO showed a neuroprotective effect on retinal damage induced by optic nerve crush in vivo. Thus, beta-secretase could be a potential target for therapy of neurodegenerative retinal diseases.
Research and Development Center, Santen Pharmaceutical Co. Ltd., 8916-16 Takayama-cho, Ikoma 630-0101, Japan.
Rie
R
Yamamoto
Shinji
S
Yoneda
Hideaki
H
Hara
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D010450:Endopeptidases / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005452:Fluoresceins / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D018698:Glutamic Acid / Q000633:toxicity; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000187:drug effects*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D005452:Fluoresceins; D005456:Fluorescent Dyes; C495708:N-benzyloxycarbonyl-valyl-leucyl-leucinal; D018696:Neuroprotective Agents; D009842:Oligopeptides; D011810:Quinoxalines; C495709:glutamyl-valyl-asparagyl-statine-valyl-alanyl-glutamyl-phenylalaninamide; C085925:calcein AM; D018698:Glutamic Acid; C056723:FG 9041; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases