Topiramate reduces excitotoxic and ischemic injury in the rat retina.
The effects of topiramate, a drug used clinically as an anti-epileptic, were investigated in excitotoxin-induced neurotoxicity models involving two different retinal primary cultures and in a rat model of retinal ischemic injury. For the in vitro studies, we used retinal-neuron cultures from rat embryos and purified retinal ganglion cells (RGCs) from newborn rats. In the retinal-neuron cultures, neurotoxicity was induced by a 10-min exposure to 1 mM glutamate or (+/-)-a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). In RGCs, neurotoxicity was induced by incubation for 3 days in a culture medium containing 25 microM glutamate. For the in vivo study, retinal ischemia was induced by elevating intraocular pressure to 130 mmHg for 45 min, and topiramate was administered intraperitoneally before and after the ischemia. Retinal damage was evaluated by measuring the number of cells in the ganglion cell layer (GCL) and the thickness of the inner plexiform layer (IPL), and by examining the a- and b-waves of the electroretinogram (ERG). Topiramate (> or =1 microM) markedly reduced the neuronal cell death induced by each of the excitotoxins in rat retinal-neuron cultures and in RGCs. Ischemia caused a decrease in GCL cells and in IPL thickness, and a diminution of the ERG waves. Histopathologic and functional analyses indicated that systemic treatment with topiramate prevented ischemia-induced damage in a dose-dependent manner. In conclusion, topiramate was protective against excitotoxic and ischemic retinal-neuron damage in vitro and in vivo, respectively. Therefore, it may be useful for treatment of the retina-related diseases such as central retinal artery occlusion, diabetic retinopathy, and glaucoma.
Yoneda
Shinji
S
Glaucoma Group, Research and Development Division, Santen Pharmaceutical Co. Ltd., 8916-16, Takayama, Ikoma 630-0101, Japan.
Tanaka
Etsuko
E
Goto
Wakana
W
Ota
Takashi
T
Hara
Hideaki
H
D000818:Animals; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012160:Retina / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D000077236:Topiramate
D018690:Excitatory Amino Acid Agonists; D000077236:Topiramate; D005632:Fructose