title: Neuroprotective effect against axonal damage-induced retinal ganglion cell death in apolipoprotein E-deficient mice through the suppression of kainate receptor signaling.
abstract: Apolipoprotein E (ApoE) plays important roles in the body, including a carrier of cholesterols, an anti-oxidant, and a ligand for the low-density lipoprotein receptors. In the nervous system, the presence of ApoE4 isoforms is associated with Alzheimer's disease. ApoE gene polymorphisms are also associated with glaucoma, but the function of ApoE in the retina remains unclear. In this study, we investigated the role of ApoE in axonal damage-induced RGC death. ApoE was detected in the astrocytes and Müller cells in the wild-type (WT) retina. RGC damage was induced in adult ApoE-deficient mice (male, 10-12 weeks old) through ocular hypertension (OH), optic nerve crush (NC), or by administering kainic acid (KA) intravitreally. The WT mice were treated with a glutamate receptor antagonist (MK801 or CNQX) 30 min before performing NC or left untreated. Seven days later, the retinas were flat mounted and Fluorogold-labeled RGCs were counted. We found that the RGCs in the ApoE-deficient mice were resistant to OH-induced RGC death and optic nerve degeneration 4 weeks after induction. In WT mice, NC effectively induced RGC death (control: 4085±331 cells/mm(2), NC: 1728±170 cells/mm(2)). CNQX, an inhibitor of KA receptors, suppressed this RGC death (3031±246 cells/mm(2)), but MK801, an inhibitor of NMDA receptors, did not (1769±212 cells/mm(2)). This indicated the involvement of KA receptor signaling in NC-induced RGC death. We found that NC- or KA-induced RGC death was significantly less in the ApoE-deficient mice than in the WT mice. These data suggest that the ApoE deficiency had a neuroprotective effect against axonal damage-induced RGC death by suppressing the KA receptor signaling.
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kazuko
authors.initials: K
authors.lastname: Omodaka
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Koji M
authors.initials: KM
authors.lastname: Nishiguchi
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yasuda
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Orie
authors.initials: O
authors.lastname: Nakamura
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.affiliation: Department of Ophthalmology and Visual Science, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; Department of Advanced Ophthalmic Medicine, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; Department of Retinal Disease Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan. Electronic address: ntoru@oph.med.tohoku.ac.jp.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000627:therapeutic use; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000627:therapeutic use; D009798:Ocular Hypertension / Q000150:complications; D020221:Optic Nerve Injuries / Q000150:complications; D018092:Kainic Acid Receptors / Q000378:metabolism*; D012162:Retinal Degeneration / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013266:Stilbamidines
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001057:Apolipoproteins E; D016291:Dizocilpine Maleate; D007608:Kainic Acid; D018696:Neuroprotective Agents; D018092:Kainic Acid Receptors; D013266:Stilbamidines; C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt
keywords: Astrocyte; Excitotoxicity; Glaucoma; Optic nerve; Retinal ganglion cell