title: Hypoxia-induced retinal ganglion cell death and the neuroprotective effects of beta-adrenergic antagonists.
abstract: Hypoxia-induced retinal ganglion cell (RGC) death has been implicated in glaucomatous optic neuropathy. However, the precise mechanism of death signaling and how neuroprotective agents affect it are still unclear. The aim of this study is to characterize the mechanisms of hypoxia-induced apoptosis of cultured purified RGCs and to study the neuroprotective effects of beta-adrenergic antagonists. Rat RGCs were purified utilizing a modified two-step immuno-panning procedure. First, the extent of apoptosis in RGCs under hypoxia was quantified. Next, the effects of glutamate-channel antagonists (MK801 or DNQX), Bax inhibiting peptide (BIP), and beta-adrenergic antagonists (betaxolol, nipradilol, timolol or carteolol) on hypoxia-induced RGC death were investigated by the cell viability assay. Third, the effects of beta-adrenergic antagonists on hypoxia-induced increase of intracellular calcium concentrations ([Ca(2+)](i)) and the additional effect of NO scavenger to nipradilol were evaluated. Apoptotic RGC percentages under hypoxia were significantly increased compared to the control. The viability of RGCs under hypoxia was not affected by MK801 or DNQX, whereas it was increased in a dose-dependent manner with exposure to BIP, and to betaxolol, nipradilol, timolol, but not to carteolol. These effective beta-adrenergic antagonists showed no significant change in hypoxia-induced [Ca(2+)](i) levels. The NO scavenger alleviated neuroprotective effect by nipradilol. In conclusion, purified RGC damage induced by hypoxia involves Bax-dependent apoptotic pathway, but mostly independent of glutamate receptor-mediated excitotoxicity. Betaxolol, timolol and nipradilol showed a protective effect against hypoxia-induced RGC death, which was thought to be irrelevant either to calcium channel or beta-adrenoceptor blocking effects.
authors: Department of Ophthalmology, University of Tokyo School of Medicine, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
authors: Yi-Ning
authors: YN
authors: Chen
authors: Hideyuki
authors: H
authors: Yamada
authors: Wei
authors: W
authors: Mao
authors: Shigemi
authors: S
authors: Matsuyama
authors: Makoto
authors: M
authors: Aihara
authors: Makoto
authors: M
authors: Araie
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D005901:Glaucoma / Q000150:complications* / Q000503:physiopathology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D051381:Rats; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000319:Adrenergic beta-Antagonists; D018691:Excitatory Amino Acid Antagonists; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D010455:Peptides; D017470:Receptors, Glutamate; D051028:bcl-2-Associated X Protein; D002118:Calcium