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The Journal of Neuroscience, March 2, 2005, 25(9):2396-2404; doi:10.1523/JNEUROSCI.4866-04.2005

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Development/Plasticity/Repair
Cytoprotective Effects of Geranylgeranylacetone against Retinal Photooxidative Damage

Masaki Tanito,^1,2 Yong-Won Kwon,¹ Norihiko Kondo,¹ Jie Bai,¹ Hiroshi Masutani,¹ Hajime Nakamura,³ Junichi Fujii,⁴ Akihiro Ohira,² and Junji Yodoi¹

¹Department of Biological Responses, Institute for Virus Research, Kyoto University, Kyoto 606-8507, Japan, ²Department of Ophthalmology, Shimane University School of Medicine, Shimane 693-8501, Japan, ³Thioredoxin Project, Department of Experimental Therapeutics, Translational Research Center, Kyoto University Hospital, Kyoto 606-8507, Japan, and ⁴Department of Biochemistry, Yamagata University, Yamagata 990-9585, Japan

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 µM) induced intracellular Trx, Hsp72, and extracellular Trx but not extracellular Hsp72. Extracellular Trx (0.75 nM) attenuated H₂O₂ (200 µM)-induced cell damage in 661W cells. Pretreatment with GGA and overexpression of Trx in K-1034 cells counteracted H₂O₂ (50 µM)-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.

Key words: retinal light damage; geranylgeranylacetone; GGA; thioredoxin; Trx; heat shock protein 72; Hsp72; neurotrophic factor; phagocytosis

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Received July 30, 2004; revised January 6, 2005; accepted January 7, 2005.

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