title: P2X7 receptor antagonists protect against N-methyl-D-aspartic acid-induced neuronal injury in the rat retina.
abstract: Activation of N-methyl-d-aspartic acid (NMDA) receptors followed by a large Ca(2+) influx is thought to be a mechanism of glaucoma-induced neuronal cell death. It is possible that damage-associated molecular patterns leak from injured cells, such as adenosine triphosphate, causing retinal ganglion cell death in glaucoma. In the present study, we histologically investigated whether antagonists of the P2X7 receptor protected against NMDA-induced retinal injury in the rat in vivo. Under ketamine/xylazine anesthesia, male Sprague-Dawley rats were subjected to intravitreal injection of NMDA. We used A438079 (3-(5-(2,3-dichlorophenyl)-1H-tetrazol-1-yl)methyl pyridine) and brilliant blue G as P2X7 receptor antagonists. Upon morphometric evaluation 7 days after an intravitreal injection (200 nmol/eye), NMDA-induced cell loss was apparent in the ganglion cell layer. Intravitreal A438079 (50 pmol/eye) simultaneously injected with NMDA and intraperitoneal brilliant blue G (50 mg/kg) administered just before the NMDA injection as well as 24 and 48h after significantly reduced cell loss. In addition, A438079 decreased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells 12h after NMDA injection. P2X7 receptors were immunolocalized in the ganglion cell layer and the inner and outer plexiform layers, whereas the immunopositive P2X7 receptor signal was not detected on the Iba1-positive microglial cells that infiltrated the retina 12h after NMDA injection. The present study shows that stimulation of the P2X7 receptor is involved in NMDA-induced histological damage in the rat retina in vivo. P2X7 receptor antagonists may be effective in preventing retinal diseases caused by glutamate excitotoxicity, such as glaucoma and retinal artery occlusion.
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan. Electronic address: sakamotok@pharm.kitasato-u.ac.jp.
authors: Kenji
authors: K
authors: Sakamoto
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Kanako
authors: K
authors: Endo
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Taishi
authors: T
authors: Suzuki
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Kyosuke
authors: K
authors: Fujimura
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Yuki
authors: Y
authors: Kurauchi
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Asami
authors: A
authors: Mori
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Tsutomu
authors: T
authors: Nakahara
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Kunio
authors: K
authors: Ishii
mesh_terms: D000255:Adenosine Triphosphate / Q000009:adverse effects / Q000031:analogs & derivatives; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D016202:N-Methylaspartate / Q000009:adverse effects*; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D058486:Receptors, Purinergic P2X7; C033901:3'-O-(4-benzoyl)benzoyladenosine 5'-triphosphate; D016202:N-Methylaspartate; D000255:Adenosine Triphosphate
keywords: N-methyl-d-aspartic acid; Neuronal cell death; P2X7 receptor; Retina