title: Critical neuroprotective roles of heme oxygenase-1 induction against axonal injury-induced retinal ganglion cell death.
abstract: Although axonal damage induces significant retinal ganglion cell (RGC) death, small numbers of RGCs are able to survive up to 7 days after optic nerve crush (NC) injury. To develop new treatments, we set out to identify patterns of change in the gene expression of axonal damage-resistant RGCs. To compensate for the low density of RGCs in the retina, we performed retrograde labeling of these cells with 4Di-10ASP in adult mice and 7 days after NC purified the RGCs with fluorescence-activated cell sorting. Gene expression in the cells was determined with a microarray, and the expression of Ho-1 was determined with quantitative PCR (qPCR). Changes in protein expression were assessed with immunohistochemistry and immunoblotting. Additionally, the density of Fluoro-gold-labeled RGCs was counted in retinas from mice pretreated with CoPP, a potent HO-1 inducer. The microarray and qPCR analyses showed increased expression of Ho-1 in the post-NC RGCs. Immunohistochemistry also showed that HO-1-positive cells were present in the ganglion cell layer (GCL), and cell counting showed that the proportion of HO-1-positive cells in the GCL rose significantly after NC. Seven days after NC, the number of RGCs in the CoPP-treated mice was significantly higher than in the control mice. Combined pretreatment with SnPP, an HO-1 inhibitor, suppressed the neuroprotective effect of CoPP. These results reflect changes in HO-1 activity to RGCs that are a key part of RGC survival. Upregulation of HO-1 signaling may therefore be a novel therapeutic strategy for glaucoma.
authors.affiliation: Department of Ophthalmology, Tohoku University Graduate School of Medicine, Miyagi, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Himori
authors.forename: Kazuichi
authors.initials: K
authors.lastname: Maruyama
authors.forename: Kotaro
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yasuda
authors.forename: Morin
authors.initials: M
authors.lastname: Ryu
authors.forename: Kazuko
authors.initials: K
authors.lastname: Omodaka
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Shiga
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Toru
authors.initials: T
authors.lastname: Nakazawa
mesh_terms: D000818:Animals; D001369:Axons / Q000473:pathology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D020411:Oligonucleotide Array Sequence Analysis; D020221:Optic Nerve Injuries / Q000188:drug therapy / Q000473:pathology*; D011524:Protoporphyrins; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use; D012165:Retinal Ganglion Cells / Q000473:pathology*; D018709:Statistics, Nonparametric; D013266:Stilbamidines; D013997:Time Factors
chemical_list: C049774:2-hydroxy-4,4'-diamidinostilbene, methanesulfonate salt; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011524:Protoporphyrins; D011719:Pyrazines; D011758:Pyrroles; D013266:Stilbamidines; C484301:cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine; C007095:cobaltiprotoporphyrin; D051547:Heme Oxygenase-1
keywords: glaucoma; heme oxygenase-1; neuroprotection; retinal ganglion cell