Cytoprotective effects of geranylgeranylacetone against retinal photooxidative damage.
Exposure to excessive light induces retinal photoreceptor cell damage, leading to development and progression of various retinal diseases. We tested the effect of geranylgeranylacetone (GGA), an acyclic polyisoprenoid, on light-induced retinal damage in mice. Oral treatment with GGA (1.0 mg/d) for 5 d induced thioredoxin (Trx) and heat shock protein 72 (Hsp72) predominantly in the retinal pigment epithelium (RPE). After white light exposure (8000 lux for 2 h), the percentage of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive photoreceptor cells decreased significantly at 24 and 96 h, and the number of photoreceptor cell nuclei at 96 h and the electroretinographic amplitudes of the a- and b-waves at 4 and 10 d increased significantly in GGA-pretreated mice compared with saline-pretreated mice. Light-induced upregulations of 8-hydroxy-2-deoxyguanosine and 4-hydroxy-2-nonenal-modified protein, markers of oxidative stress, were inhibited by GGA pretreatment. To elucidate the cytoprotective mechanism of GGA and Trx, we used human K-1034 RPE cells and mouse photoreceptor-derived 661W cells. In K-1034 cells, GGA (10 microM) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 nM) attenuated H2O2 (200 microM)-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H2O2 (50 microM)-induced attenuation of cellular latex bead incorporation. Protection of phagocytotic activity through induction of Trx and possibly Hsp72 in RPE cells and elimination of oxidative stress in the photoreceptor layer through release of Trx from RPE cells may be mechanisms of GGA-mediated cytoprotection. Therefore, Trx is a neurotrophic factor released from RPE cells and plays a crucial role in maintaining photoreceptor cell integrity.
Tanito
Masaki
M
Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan.
Kwon
Yong-Won
YW
Kondo
Norihiko
N
Bai
Jie
J
Masutani
Hiroshi
H
Nakamura
Hajime
H
Fujii
Junichi
J
Ohira
Akihiro
A
Yodoi
Junji
J
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000627:therapeutic use*; D004596:Electroretinography / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005434:Flow Cytometry / Q000379:methods; D015870:Gene Expression / Q000187:drug effects; D050884:HSP72 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007150:Immunohistochemistry / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D008027:Light / Q000009:adverse effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009363:Neoplasm Proteins / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010586:Phagocytes / Q000187:drug effects; D010786:Photoreceptor Cells / Q000187:drug effects* / Q000528:radiation effects; D012164:Retinal Diseases / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D013879:Thioredoxins / Q000378:metabolism; D013997:Time Factors
D000447:Aldehydes; D004224:Diterpenes; D050884:HSP72 Heat-Shock Proteins; D009363:Neoplasm Proteins; D018696:Neuroprotective Agents; D013879:Thioredoxins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D006861:Hydrogen Peroxide; D003849:Deoxyguanosine; C027576:4-hydroxy-2-nonenal; C031049:geranylgeranylacetone
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