title: Apelin-36 is protective against N-methyl-D-aspartic-acid-induced retinal ganglion cell death in the mice.
abstract: Retinal ganglion cell death in glaucoma is caused at least in part by a large Ca2+influx through N-methyl-D-aspartic acid (NMDA) receptors. Apelin is a peptide originally found in the tissue extracts of bovine stomach. Recent studies have been shown that apelin protects against the ischemic-reperfused injury in the brain. We examined whether apelin had protective effects on the NMDA-induced retinal ganglion cell (RGC) death using B6.Cg-TgN(Thy1-CFP)23Jrs/J transgenic mice, which express the enhanced cyan fluorescent protein in RGCs in the retina, in vivo. The mice were anesthetized by ketamine and xylazine, and NMDA (40 nmol/eye) was intravitreally injected. We evaluated the effects of apelin-13, [Glp1]-apelin-13, a potent agonist of apelin receptor, and apelin-36 on the NMDA-induced retinal ganglion cell death. NMDA-induced retinal ganglion cell loss was clearly seen 7 days after NMDA injection. Intravitreal apelin-36 (0.33 nmol/eye), but not apelin-13 (1 nmol/eye) nor [Glp1]-apelin-13 (1 nmol/eye), simultaneously injected with NMDA significantly reduced the cell loss. The protective effect of apelin-36 was not reduced by ML221 (0.1 nmol/eye; 5-[(4-Nitrobenzoyl)oxy]-2-[(2-pyrimidinylthio)methyl]-4H-pyran-4-one), an apelin receptor antagonist, GF109203X (0.03 nmol/eye), a protein kinase C inhibitor, U0126 (0.2 nmol/eye), a MAPK/ERK kinase inhibitor, LY294002 (0.1 nmol/eye), a phosphoinositide 3-kinase inhibitor, Akti 1/2 (0.05 nmol/eye), an Akt inhibitor, or 4,5,6,7-tetrabromobenzotriazole (0.2 nmol/eye), a casein kinase-2 inhibitor. In addition, human apelin-36 did not affect the kainic-acid (20 nmol/eye)-induced ganglion cell death. The present study suggests that apelin-36 protects against the NMDA-induced ganglion cell death independently of the activation of apelin receptor in the murine retina in vivo.
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: Yuta
authors: Y
authors: Murakami
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Shohei
authors: S
authors: Sawada
authors: Department of Molecular Pharmacology, Kitasato University School of Pharmaceutical Sciences, Tokyo 108-8641, Japan.
authors: Hiroko
authors: H
authors: Ushikubo
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: D000818:Animals; D000075244:Apelin Receptors; D002352:Carrier Proteins / Q000378:metabolism; D047390:Casein Kinase II / Q000037:antagonists & inhibitors; D016923:Cell Death / Q000187:drug effects; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000737:chemistry / Q000494:pharmacology*; D007608:Kainic Acid / Q000009:adverse effects; D008297:Male; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000009:adverse effects*; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D059748:Proteolysis / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D012165:Retinal Ganglion Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D013049:Spectrin
chemical_list: D000075244:Apelin Receptors; D002352:Carrier Proteins; D047390:Casein Kinase II; D036341:Intercellular Signaling Peptides and Proteins; D007608:Kainic Acid; D008840:Microfilament Proteins; D016202:N-Methylaspartate; D018696:Neuroprotective Agents; D043562:Receptors, G-Protein-Coupled; D013049:Spectrin; C491285:Aplnr protein, mouse; C495199:apelin-13 peptide
keywords: Apelin; Apelin receptor; N-methyl-D-aspartic acid; Neuronal cell death; Retina