Protective effects of timolol against the neuronal damage induced by glutamate and ischemia in the rat retina

• Published in: Brain research 2002-12, Vol.958 (1), p.10-19
• Main Authors: Goto, Wakana, Ota, Takashi, Morikawa, Nobuo, Otori, Yasumasa, Hara, Hideaki, Kawazu, Kouichi, Miyawaki, Nobuaki, Tano, Yasuo
• Format: Article
• Language: English
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Acute Disease; Animals; Biological and medical sciences; Cell Death - drug effects; Cell Death - physiology; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Electroretinography; Excitatory Amino Acid Antagonists - pharmacology; Fetus; Glaucoma - drug therapy; Glaucoma - metabolism; Glaucoma - physiopathology; Glutamate; Glutamic Acid - metabolism; Glutamic Acid - toxicity; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - metabolism; Hypoxia-Ischemia, Brain - physiopathology; Ischemia; Medical sciences; Neuropharmacology; Neuroprotection; Neuroprotective agent; Neuroprotective Agents - pharmacology; Pharmacology. Drug treatments; Rats; Rats, Wistar; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - physiopathology; Retina; Retinal Degeneration - drug therapy; Retinal Degeneration - metabolism; Retinal Degeneration - physiopathology; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Timolol; Timolol - pharmacology
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(02)03372-3

The purpose of this study was to determine whether timolol, an ocular hypotensive drug, has retinal neuroprotective effects in experimental in vitro and in vivo models. For in vitro studies, we used retinal neuron cultures from rat embryos and purified retinal ganglion cells (RGCs) from newborn rats. In the former, neurotoxicity was induced using 1 mM glutamate and cell viability was assessed. In RGCs, neurotoxicity was induced using 25 μM glutamate for 3 days and cell viability was assessed. For the in vivo study, we used a rat model of retinal ischemic injury induced by elevating intraocular pressure (IOP) by raising the hydrostatic pressure. The retinal damage was evaluated by counting the number of cells in the ganglion cell layer (GCL) and by examining the a- and b-waves in the electroretinogram (ERG). For the intraocular distribution study, 0.5% [ 3H]timolol was topically applied to rat eyes, and these were enucleated after various intervals and divided into parts. Each part was combusted and the radioactivity measured. Timolol (0.1 and 1 μM) markedly reduced the glutamate-induced neuronal cells in retinal neuron cultures and in RGCs. After ischemic-reperfusion, both the number of cells in the GCL and a- and b-waves in the ERG decreased; however, topically applied 0.5% timolol reduced these effects. Topically applied 0.5% timolol was detected at a concentration of ∼1 μg/g wet tissue in retina-choroid at 30 min after its application. In conclusion, timolol was effective against retinal neuron damage both in vitro and in vivo. Furthermore, topically applied timolol reached the retina-choroid. These findings suggest that timolol has a direct neuroprotective effect against retinal damage.