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• W2055642010 abstract "Compromised clearance of all-trans-retinal (atRAL), a component of the retinoid cycle, increases the susceptibility of mouse retina to acute light-induced photoreceptor degeneration. Abca4−/−Rdh8−/− mice featuring defective atRAL clearance were used to examine the one or more underlying molecular mechanisms, because exposure to intense light causes severe photoreceptor degeneration in these animals. Here we report that bright light exposure of Abca4−/−Rdh8−/− mice increased atRAL levels in the retina that induced rapid NADPH oxidase-mediated overproduction of intracellular reactive oxygen species (ROS). Moreover, such ROS generation was inhibited by blocking phospholipase C and inositol 1,4,5-trisphosphate-induced Ca2+ release, indicating that activation occurs upstream of NADPH oxidase-mediated ROS generation. Because multiple upstream G protein-coupled receptors can activate phospholipase C, we then tested the effects of antagonists of serotonin 2A (5-HT2AR) and M3-muscarinic (M3R) receptors and found they both protected Abca4−/−Rdh8−/− mouse retinas from light-induced degeneration. Thus, a cascade of signaling events appears to mediate the toxicity of atRAL in light-induced photoreceptor degeneration of Abca4−/−Rdh8−/− mice. A similar mechanism may be operative in human Stargardt disease and age-related macular degeneration. Compromised clearance of all-trans-retinal (atRAL), a component of the retinoid cycle, increases the susceptibility of mouse retina to acute light-induced photoreceptor degeneration. Abca4−/−Rdh8−/− mice featuring defective atRAL clearance were used to examine the one or more underlying molecular mechanisms, because exposure to intense light causes severe photoreceptor degeneration in these animals. Here we report that bright light exposure of Abca4−/−Rdh8−/− mice increased atRAL levels in the retina that induced rapid NADPH oxidase-mediated overproduction of intracellular reactive oxygen species (ROS). Moreover, such ROS generation was inhibited by blocking phospholipase C and inositol 1,4,5-trisphosphate-induced Ca2+ release, indicating that activation occurs upstream of NADPH oxidase-mediated ROS generation. Because multiple upstream G protein-coupled receptors can activate phospholipase C, we then tested the effects of antagonists of serotonin 2A (5-HT2AR) and M3-muscarinic (M3R) receptors and found they both protected Abca4−/−Rdh8−/− mouse retinas from light-induced degeneration. Thus, a cascade of signaling events appears to mediate the toxicity of atRAL in light-induced photoreceptor degeneration of Abca4−/−Rdh8−/− mice. A similar mechanism may be operative in human Stargardt disease and age-related macular degeneration. To sustain vision, all-trans-retinal (atRAL), 2The abbreviations used are: atRALall-trans-retinalatROLall-trans-retinolatRAall-trans-retinoic acidA2Ediretinoid-pyridinium-ethanolamine2-APB2-aminoethoxydiphenyl borate4-DAMP1,1-dimethyl-4-diphenylacetoxypiperidinium iodide5-HT2ARserotonin 2A receptor11-cis-RAL11-cis-retinal8-OH-DPAT8-hydroxy-N,N-dipropyl-2-aminotetralinABCA4/ABCRphotoreceptor specific ATP-binding cassette transporterAPOapocyninDCF-DA2′,7′-dichlorofluorescein diacetateDHEdihydroethidiumDPIdiphenyleneiodoniumGPCRG protein-coupled receptorIP3inositol 1,4,5-trisphosphateIP3RIP3 receptorM3RM3-muscarinic receptorOCToptical coherence tomographyONHoptic nerve headONLouter nuclear layerPLCphospholipase CRet-NH2retinylamineROSreactive oxygen speciesRPEretinal pigmented epitheliumERGelectroretinogram. released from light-activated visual pigments, including rhodopsin, must be continuously isomerized back to its 11-cis isomer (1Palczewski K. G protein-coupled receptor rhodopsin.Annu. Rev. Biochem. 2006; 75: 743-767Crossref PubMed Scopus (571) Google Scholar). This process occurs by a sequence of reactions catalyzed by membrane-bound enzymes of the retinoid cycle located in rod and cone photoreceptor cell outer segments and the retinal pigmented epithelium (RPE) (2von Lintig J. Kiser P.D. Golczak M. Palczewski K. The biochemical and structural basis for trans-to-cis isomerization of retinoids in the chemistry of vision.Trends Biochem. Sci. 2010; 35: 400-410Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar, 3Travis G.H. Golczak M. Moise A.R. Palczewski K. Diseases caused by defects in the visual cycle. Retinoids as potential therapeutic agents.Annu. Rev. Pharmacol. Toxicol. 2007; 47: 469-512Crossref PubMed Scopus (329) Google Scholar, 4Kiser P.D. Golczak M. Maeda A. Palczewski K. Biochim. Biophys. Acta. 2011; PubMed Google Scholar, 5Kiser P.D. Palczewski K. Membrane-binding and enzymatic properties of RPE65.Prog. Retin. Eye Res. 2010; 29: 428-442Crossref PubMed Scopus (50) Google Scholar). Regeneration of rhodopsin requires 11-cis-retinal (11-cis-RAL) supplied from the RPE, but cone pigments are also regenerated in cone-dominant species by a separate “cone visual cycle” (6Jones G.J. Crouch R.K. Wiggert B. Cornwall M.C. Chader G.J. Retinoid requirements for recovery of sensitivity after visual-pigment bleaching in isolated photoreceptors.Proc. Natl. Acad. Sci. U.S.A. 1989; 86: 9606-9610Crossref PubMed Scopus (161) Google Scholar, 7Mata N.L. Radu R.A. Clemmons R.C. Travis G.H. Isomerization and oxidation of vitamin a in cone-dominant retinas. A novel pathway for visual-pigment regeneration in daylight.Neuron. 2002; 36: 69-80Abstract Full Text Full Text PDF PubMed Scopus (309) Google Scholar, 8Fleisch V.C. Schonthaler H.B. von Lintig J. Neuhauss S.C. Subfunctionalization of a retinoid-binding protein provides evidence for two parallel visual cycles in the cone-dominant zebrafish retina.J. Neurosci. 2008; 28: 8208-8216Crossref PubMed Scopus (54) Google Scholar). A high flux of retinoids through the retinoid cycle, as occurs during intense light exposure, can cause elevated levels of toxic retinoid intermediates, especially atRAL, that can induce photoreceptor degeneration (9Rózanowska M. Sarna T. Light-induced damage to the retina. Role of rhodopsin chromophore revisited.Photochem. Photobiol. 2005; 81: 1305-1330Crossref PubMed Scopus (145) Google Scholar). Toxic effects of atRAL include caspase activation and mitochondrial-associated cell death (10Maeda A. Maeda T. Golczak M. Chou S. Desai A. Hoppel C.L. Matsuyama S. Palczewski K. Involvement of all-trans-retinal in acute light-induced retinopathy of mice.J. Biol. Chem. 2009; 284: 15173-15183Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar), but the precise sequence of molecular events that leads to photoreceptor degeneration remains to be clarified. all-trans-retinal all-trans-retinol all-trans-retinoic acid diretinoid-pyridinium-ethanolamine 2-aminoethoxydiphenyl borate 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide serotonin 2A receptor 11-cis-retinal 8-hydroxy-N,N-dipropyl-2-aminotetralin photoreceptor specific ATP-binding cassette transporter apocynin 2′,7′-dichlorofluorescein diacetate dihydroethidium diphenyleneiodonium G protein-coupled receptor inositol 1,4,5-trisphosphate IP3 receptor M3-muscarinic receptor optical coherence tomography optic nerve head outer nuclear layer phospholipase C retinylamine reactive oxygen species retinal pigmented epithelium electroretinogram. Even in the presence of a functional retinoid cycle, A2E, a retinal dimer, and other toxic atRAL condensation products (11Mata N.L. Weng J. Travis G.H. Biosynthesis of a major lipofuscin fluorophore in mice and humans with ABCR-mediated retinal and macular degeneration.Proc. Natl. Acad. Sci. U.S.A. 2000; 97: 7154-7159Crossref PubMed Scopus (395) Google Scholar, 12Kim Y.K. Wassef L. Hamberger L. Piantedosi R. Palczewski K. Blaner W.S. Quadro L. Retinyl ester formation by lecithin. Retinol acyltransferase is a key regulator of retinoid homeostasis in mouse embryogenesis.J. Biol. Chem. 2008; 283: 5611-5621Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar, 13Fishkin N. Yefidoff R. Gollipalli D.R. Rando R.R. On the mechanism of isomerization of all-trans-retinol esters to 11-cis-retinol in retinal pigment epithelial cells. 11-Fluoro-all-trans-retinol as substrate/inhibitor in the visual cycle.Bioorg. Med. Chem. 2005; 13: 5189-5194Crossref PubMed Scopus (12) Google Scholar) accumulate with age (14Yannuzzi L.A. Ober M.D. Slakter J.S. Spaide R.F. Fisher Y.L. Flower R.W. Rosen R. Ophthalmic fundus imaging. Today and beyond.Am. J. Ophthalmol. 2004; 137: 511-524Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar). These compounds are fluorescent biomarkers of aberrant atRAL metabolism (15Palczewska G. Maeda T. Imanishi Y. Sun W. Chen Y. Williams D.R. Piston D.W. Maeda A. Palczewski K. Noninvasive multiphoton fluorescence microscopy resolves retinol and retinal condensation products in mouse eyes.Nat. Med. 2010; 16: 1444-1449Crossref PubMed Scopus (65) Google Scholar). Patients affected by retinal degeneration in age-related macular degeneration, Stargardt disease, or some other retinal diseases feature abnormal accumulation of these atRAL condensation products (16Allikmets R. Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium.Am. J. Hum. Genet. 2000; 67: 487-491Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). Mice carrying a double knock-out of the Rdh8 gene, which encodes one of the main enzymes that reduces atRAL in rod and cone outer segments (17Rattner A. Smallwood P.M. Nathans J. Identification and characterization of all-trans-retinol dehydrogenase from photoreceptor outer segments, the visual cycle enzyme that reduces all-trans-retinal to all-trans-retinol.J. Biol. Chem. 2000; 275: 11034-11043Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar), and the Abca4 gene (18Molday R.S. Beharry S. Ahn J. Zhong M. Binding of N-retinylidene-PE to ABCA4 and a model for its transport across membranes.Adv. Exp. Med. Biol. 2006; 572: 465-470Crossref PubMed Google Scholar, 19Tsybovsky Y. Wang B. Quazi F. Molday R.S. Palczewski K. Posttranslational modifications of the photoreceptor-specific ABC transporter ABCA4.Biochemistry. 2011; 50: 6855-6866Crossref PubMed Scopus (31) Google Scholar), which encodes the transporter of atRAL from the inside to the outside of disc membranes, rapidly accumulate atRAL condensation products and manifest RPE/photoreceptor dystrophy at an early age (20Maeda A. Maeda T. Golczak M. Palczewski K. Retinopathy in mice induced by disrupted all-trans-retinal clearance.J. Biol. Chem. 2008; 283: 26684-26693Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). The similarity of this retinopathy to human age-related macular degeneration makes these Abca4−/−Rdh8−/− mice invaluable for research aimed at ameliorating this devastating blinding disease (10Maeda A. Maeda T. Golczak M. Chou S. Desai A. Hoppel C.L. Matsuyama S. Palczewski K. Involvement of all-trans-retinal in acute light-induced retinopathy of mice.J. Biol. Chem. 2009; 284: 15173-15183Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 21Maeda A. Golczak M. Chen Y. Okano K. Kohno H. Shiose S. Ishikawa K. Harte W. Palczewska G. Maeda T. Palczewski K. Nature Chem. Biol. 2011; 8: 170-178Crossref PubMed Scopus (111) Google Scholar). Mutations in ABCA4 can cause Stargardt macular degeneration (22Allikmets R. Singh N. Sun H. Shroyer N.F. Hutchinson A. Chidambaram A. Gerrard B. Baird L. Stauffer D. Peiffer A. Rattner A. Smallwood P. Li Y. Anderson K.L. Lewis R.A. Nathans J. Leppert M. Dean M. Lupski J.R. A photoreceptor cell-specific ATP-binding transporter gene (ABCR) is mutated in recessive Stargardt macular dystrophy.Nat. Genet. 1997; 15: 236-246Crossref PubMed Scopus (1122) Google Scholar), cone-rod dystrophy (23Cremers F.P. van de Pol D.J. van Driel M. den Hollander A.I. van Haren F.J. Knoers N.V. Tijmes N. Bergen A.A. Rohrschneider K. Blankenagel A. Pinckers A.J. Deutman A.F. Hoyng C.B. Autosomal recessive retinitis pigmentosa and cone-rod dystrophy caused by splice site mutations in the Stargardt's disease gene ABCR.Hum Mol Genet. 1998; 7: 355-362Crossref PubMed Scopus (465) Google Scholar), or recessive retinitis pigmentosa (24Martínez-Mir A. Paloma E. Allikmets R. Ayuso C. del Rio T. Dean M. Vilageliu L. Gonzàlez-Duarte R. Balcells S. Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR.Nat. Genet. 1998; 18: 11-12Crossref PubMed Scopus (333) Google Scholar, 25Zhang Q. Zulfiqar F. Xiao X. Riazuddin S.A. Ayyagari R. Sabar F. Caruso R. Sieving P.A. Riazuddin S. Hejtmancik J.F. Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3-p21.2 between D1S2896 and D1S457 but outside ABCA4.Hum Genet. 2005; 118: 356-365Crossref PubMed Scopus (24) Google Scholar). Heterozygous mutations in ABCA4 increase the risk of developing age-related macular degeneration as well (16Allikmets R. Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium.Am. J. Hum. Genet. 2000; 67: 487-491Abstract Full Text Full Text PDF PubMed Scopus (259) Google Scholar). Abca4−/−Rdh8−/− mice, which exhibits markedly delayed clearance of atRAL after photobleaching and serves as a model of cone and rod retinal degeneration (10Maeda A. Maeda T. Golczak M. Chou S. Desai A. Hoppel C.L. Matsuyama S. Palczewski K. Involvement of all-trans-retinal in acute light-induced retinopathy of mice.J. Biol. Chem. 2009; 284: 15173-15183Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar, 21Maeda A. Golczak M. Chen Y. Okano K. Kohno H. Shiose S. Ishikawa K. Harte W. Palczewska G. Maeda T. Palczewski K. Nature Chem. Biol. 2011; 8: 170-178Crossref PubMed Scopus (111) Google Scholar), allowed us to examine in greater detail the molecular pathways involved in the pathogenesis of this retinopathy. Oxidative stress is a major mechanism contributing to photoreceptor cell death in animal models of retinal degeneration, including light-induced retinopathy (26Donovan M. Carmody R.J. Cotter T.G. Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3-independent.J. Biol. Chem. 2001; 276: 23000-23008Abstract Full Text Full Text PDF PubMed Scopus (153) Google Scholar, 27Organisciak D.T. Darrow R.M. Jiang Y.I. Marak G.E. Blanks J.C. Protection by dimethylthiourea against retinal light damage in rats.Invest. Ophthalmol. Vis. Sci. 1992; 33: 1599-1609PubMed Google Scholar). Tightly regulated low levels of reactive oxygen species (ROS) are needed to mediate physiological functions, including cell survival, growth, differentiation, and metabolism. But excessive production of ROS can damage macromolecules, including DNA, proteins, and lipids (28Finkel T. Oxidant signals and oxidative stress.Curr. Opin. Cell Biol. 2003; 15: 247-254Crossref PubMed Scopus (1229) Google Scholar). Thus, aberrant ROS generation constitutes a major mechanism of pathological cell death. NADPH oxidase is the main enzymatic source of superoxide and hydrogen peroxide (29Lambeth J.D. NOX enzymes and the biology of reactive oxygen.Nat. Rev. Immunol. 2004; 4: 181-189Crossref PubMed Scopus (2492) Google Scholar), and its product ROS, which is involved in retinal degeneration (30Haruta M. Bush R.A. Kjellstrom S. Vijayasarathy C. Zeng Y. Le Y.Z. Sieving P.A. Depleting Rac1 in mouse rod photoreceptors protects them from photo-oxidative stress without affecting their structure or function.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 9397-9402Crossref PubMed Scopus (47) Google Scholar, 31Usui S. Oveson B.C. Lee S.Y. Jo Y.J. Yoshida T. Miki A. Miki K. Iwase T. Lu L. Campochiaro P.A. NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa.J. Neurochem. 2009; 110: 1028-1037Crossref PubMed Scopus (110) Google Scholar). Rac1, an essential component of the NADPH oxidase complex, is implicated in light-induced retinal degeneration, because Rac1 deficiency partially protects photoreceptor cells against photo-oxidative insult (30Haruta M. Bush R.A. Kjellstrom S. Vijayasarathy C. Zeng Y. Le Y.Z. Sieving P.A. Depleting Rac1 in mouse rod photoreceptors protects them from photo-oxidative stress without affecting their structure or function.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 9397-9402Crossref PubMed Scopus (47) Google Scholar). Treatment with the NADPH oxidase inhibitor apocynin (1-(4-hydroxy-3-methoxyphenyl)ethanone (APO)) (32Stolk J. Hiltermann T.J. Dijkman J.H. Verhoeven A.J. Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol.Am. J. Respir. Cell Mol. Biol. 1994; 11: 95-102Crossref PubMed Scopus (588) Google Scholar) can protect BALB/c mice from developing light-induced retinal degeneration (30Haruta M. Bush R.A. Kjellstrom S. Vijayasarathy C. Zeng Y. Le Y.Z. Sieving P.A. Depleting Rac1 in mouse rod photoreceptors protects them from photo-oxidative stress without affecting their structure or function.Proc. Natl. Acad. Sci. U.S.A. 2009; 106: 9397-9402Crossref PubMed Scopus (47) Google Scholar). Moreover, APO is effective in preventing cone cell death in a mouse model of retinitis pigmentosa (31Usui S. Oveson B.C. Lee S.Y. Jo Y.J. Yoshida T. Miki A. Miki K. Iwase T. Lu L. Campochiaro P.A. NADPH oxidase plays a central role in cone cell death in retinitis pigmentosa.J. Neurochem. 2009; 110: 1028-1037Crossref PubMed Scopus (110) Google Scholar). These findings imply that, by causing oxidative stress, NADPH oxidase is mechanistically involved in the pathogenesis of some types of retinal degeneration. Although atRAL stimulates the production of superoxide via NADPH oxidase (33Lochner J.E. Badwey J.A. Horn W. Karnovsky M.L. All-trans-retinal stimulates superoxide release and phospholipase C activity in neutrophils without significantly blocking protein kinase C.Proc. Natl. Acad. Sci. U.S.A. 1986; 83: 7673-7677Crossref PubMed Scopus (25) Google Scholar, 34Badwey J.A. Robinson J.M. Curnutte J.T. Karnovsky M.J. Karnovsky M.L. Retinoids stimulate the release of superoxide by neutrophils and change their morphology.J. Cell. Physiol. 1986; 127: 223-228Crossref PubMed Scopus (26) Google Scholar), there are observations that such stimulation is not the result of a direct interaction between atRAL and this enzyme (35Steinbeck M.J. Hegg G.G. Karnovsky M.J. Arachidonate activation of the neutrophil NADPH-oxidase. Synergistic effects of protein phosphatase inhibitors compared with protein kinase activators.J. Biol. Chem. 1991; 266: 16336-16342Abstract Full Text PDF PubMed Google Scholar). PLC activation reportedly occurs prior to NADPH oxidase-dependent ROS production in atRAL-treated neutrophils suggesting that products of PLC enzymatic activity, diacylglycerols and inositol 1,4,5-trisphosphate (IP3), could be the intermediates involved in this pathway (33Lochner J.E. Badwey J.A. Horn W. Karnovsky M.L. All-trans-retinal stimulates superoxide release and phospholipase C activity in neutrophils without significantly blocking protein kinase C.Proc. Natl. Acad. Sci. U.S.A. 1986; 83: 7673-7677Crossref PubMed Scopus (25) Google Scholar). IP3 promotes release of Ca2+ from the endoplasmic reticulum into the cytosol through binding to an intracellular IP3-receptor, IP3R (36Bootman M.D. Collins T.J. Peppiatt C.M. Prothero L.S. MacKenzie L. De Smet P. Travers M. Tovey S.C. Seo J.T. Berridge M.J. Ciccolini F. Lipp P. Calcium signaling. An overview.Semin. Cell Dev. Biol. 2001; 12: 3-10Crossref PubMed Scopus (388) Google Scholar). This signaling pathway may underlie the previously unexplained observation that atRAL causes a rapid increase in intracellular Ca2+ (10Maeda A. Maeda T. Golczak M. Chou S. Desai A. Hoppel C.L. Matsuyama S. Palczewski K. Involvement of all-trans-retinal in acute light-induced retinopathy of mice.J. Biol. Chem. 2009; 284: 15173-15183Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar). Ca2+ signaling has also been reported to increase ROS production by NADPH oxidase (37Movitz C. Sjölin C. Dahlgren C. A rise in ionized calcium activates the neutrophil NADPH-oxidase but is not sufficient to directly translocate cytosolic p47phox or p67phox to b cytochrome containing membranes.Inflammation. 1997; 21: 531-540Crossref PubMed Scopus (10) Google Scholar). Because PLC is typically activated by G protein-coupled receptors (GPCRs) coupled to Gq protein (38Rhee S.G. Regulation of phosphoinositide-specific phospholipase C.Annu. Rev. Biochem. 2001; 70: 281-312Crossref PubMed Scopus (1227) Google Scholar), specific GPCRs could affect overall PLC activation, thus mediating atRAL- induced toxic effects. Results from cell culture experiments indicate that atRAL-induced generation of ROS can be mediated through NADPH oxidase. We further investigated the in vivo signaling mechanisms that mediate the action of atRAL in causing ROS production and light-induced photoreceptor degeneration. The results indicate that PLC activation and the resulting second messenger IP3 contribute to atRAL-induced NADPH oxidase activation. The toxic action of atRAL was also diminished by blocking serotonin 2A (5-HT2AR) or M3-muscarinic (M3R) receptors, implicating GPCR participation in the overall process. These observations raise the possibility that certain types of retinal degeneration could be prevented by therapies selectively targeting transient sequestration (buffering) of elevated atRAL, antagonizing a subset of GPCRs, or inhibiting PLC, IP3R, or NADPH oxidase, alone or in combination. Abca4−/−Rdh8−/− mice, generated and genotyped as previously described (20Maeda A. Maeda T. Golczak M. Palczewski K. Retinopathy in mice induced by disrupted all-trans-retinal clearance.J. Biol. Chem. 2008; 283: 26684-26693Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar), were used when they reached 4 to 5 weeks of age. Eight- to 12-week-old BALB/c mice were obtained from Jackson Laboratory (Bar Harbor, ME). All mice were housed in the Animal Resource Center at the School of Medicine, Case Western Reserve University, where they were routinely maintained in a 12-h light (less than 10 lux)/12-h dark cycle environment. For bright light exposure experiments, mice were dark-adapted for 24 h prior to illumination at 10,000 lux (150-watt spiral lamp, Commercial Electric) for either 30 min (Abca4−/−Rdh8−/− mice) or 2 h (BALB/c mice). Abca4−/−Rdh8−/− mouse pupils were dilated with 1% tropicamide prior to light exposure, whereas BALB/c mice did not require pupil dilation before such exposure. Analyses of retinal structural and functional changes were performed 7 days after bright light exposure. All animal-handling procedures and experiments were approved by the Institutional Animal Care and Use Committee at Case Western Reserve University. atRAL was purchased from Toronto Research Chemicals, Inc. (Toronto, Canada). All-trans-retinoic acid (atRA), apocynin (APO), diphenyliodonium (DPI), 2-aminoethoxydiphenyl borate (2-APB), ketanserin, and 8-hydroxy-N,N-dipropyl-2-aminotetralin (8-OH-DPAT) were obtained from Sigma. Pregabalin was synthesized by Ricerca Bioscience LLC (Concord, OH). A2E (39Parish C.A. Hashimoto M. Nakanishi K. Dillon J. Sparrow J. Isolation and one-step preparation of A2E and iso-A2E, fluorophores from human retinal pigment epithelium.Proc. Natl. Acad. Sci. U.S.A. 1998; 95: 14609-14613Crossref PubMed Scopus (417) Google Scholar) and all-trans-retinylamine (Ret-NH2) were synthesized as previously described (40Golczak M. Kuksa V. Maeda T. Moise A.R. Palczewski K. Positively charged retinoids are potent and selective inhibitors of the trans-cis isomerization in the retinoid (visual) cycle.Proc. Natl. Acad. Sci. U.S.A. 2005; 102: 8162-8167Crossref PubMed Scopus (107) Google Scholar). U-73122 was purchased from Calbiochem (Gibbstown, NJ). Ritanserin and 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (4-DAMP) were purchased from Tocris (Ellisville, MO). ARPE19 cells were cultured in Dulbecco's modified Eagle's medium (DMEM, low glucose) supplemented with 10% fetal bovine serum. The ROS probes, 2′,7′-dichlorofluorescein diacetate (DCF-DA, Sigma) or dihydroethidium (DHE, Invitrogen) were added in DMSO at a concentration of 400 nm (final solvent concentration, 1% v/v) after indicated pretreatments and incubated at 37 °C for 10 min before cells were thoroughly washed in phosphate-buffered saline. ROS signals were subsequently observed at the same exposure setting under an inverted fluorescence microscope (Leica DMI 6000 B). Fluorescence quantification was performed with Metamorph imaging software (Molecular Devices, Downington, PA). Thresholds corresponding to fluorescent signals were set from the images, and average fluorescence intensities were recorded for statistical analyses. The ROS probe, DHE, at a dose of 20 mg/kg body weight in 25 μl of DMSO, was administered to Abca4−/−Rdh8−/− mice via intraperitoneal injection 30 min prior to light exposure. Eye cups obtained after removing the cornea, lens, and vitreous body from enucleated eye globes 3 h post light illumination were fixed in 4% paraformaldehyde. Cryosections were prepared from fixed eye cups and cut at 12-μm thickness for microscopic assessment of ROS fluorescence in the retina using ImageJ (National Institutes of Health). Ret-NH2 and pregabalin were administered by gavage to 24-h dark-adapted mice at a dose of 100 mg/kg body weight 2 h before illumination. All other experimental compounds were given to 24 h dark-adapted mice by intraperitoneal injection through a 28-gauge needle at 24 h and 1 h prior to bright light exposure. Tested compounds and their doses were as follows: APO, 50 mg/kg body weight; DPI, 1 mg/kg body weight; U-73122, 6.25 mg/kg body weight; 2-APB, 2.5 mg/kg body weight; ketanserin, 1.25 mg/kg body weight; ritanserin, 3.75 mg/kg body weight; 8-OH-DPAT, 10 mg/kg body weight; and 4-DAMP, 6.25 mg/kg body weight. The gavage volume was 100 μl per treatment. The injected volume of the injected drug did not exceeded 50 μl per animal. Ret-NH2 was prepared in soybean oil. Pregabalin and 8-OH-DPAT were dissolved in water. All other drugs were dissolved in DMSO. Ultra-high resolution SD-Optical Coherence Tomography (OCT, Bioptigen, Research Triangle Park, NC) was used for in vivo imaging of mouse retinas. Mice were anesthetized by intraperitoneal injection of a mixture consisting of ketamine (6 mg/ml) and xylazine (0.44 mg/ml) diluted with 10 mm sodium phosphate, pH 7.2, and 100 mm NaCl given at a dose of 20 μl/g body weight. Pupils were dilated with 1% tropicamide prior to imaging. Four frames of OCT images acquired in the B-mode were averaged for presentation. Retinal histology and immunohistochemistry were performed as previously described (41Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo.J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Briefly, eye cups freed of cornea, lens, and vitreous body were fixed in 2% glutaraldehyde/4% paraformaldehyde and processed for Epon embedding. Sections of 1-μm thickness were cut and stained with toluidine blue for histological examination under a light microscope. Immunohistochemical analysis was performed on 12-μm thick cryosections prepared from 4% paraformaldehyde-fixed eye cups. Collected cryosections were stained with DAPI and subjected to examination for rhodopsin, and with peanut agglutinin for cone sheaths. All ERG procedures were performed by published methods (41Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo.J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). For single-flash recording, the duration of white light flash stimuli (from 20 μs to 1 ms) was adjusted to provide a range of illumination intensities (from −3.7 to 1.6 log cd·s/m2). Three to five recordings were made at sufficient intervals between flash stimuli (from 3 s to 1 min) to allow recovery from any photobleaching effects. Extraction, derivatization, and separation of retinoids were performed, and 11-cis-retinal content was analyzed by HPLC by procedures previously described (41Maeda A. Maeda T. Imanishi Y. Kuksa V. Alekseev A. Bronson J.D. Zhang H. Zhu L. Sun W. Saperstein D.A. Rieke F. Baehr W. Palczewski K. Role of photoreceptor-specific retinol dehydrogenase in the retinoid cycle in vivo.J. Biol. Chem. 2005; 280: 18822-18832Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar). Results were averaged from at least three independent experiments. Data were expressed as means ± S.E., and statistical analyses were performed using the student's t test for p value calculations. To determine the effect of atRAL on retinal ROS production, we incubated ARPE19 cells, an immortalized human RPE-like cell line susceptible to atRAL-induced cell death, with atRAL followed by examination with a ROS probe. As shown in Fig. 1A, atRAL exposure significantly elevated intracellular ROS production prior to massive cell death in a dose-dependent manner. Because the probe used, DCF-DA, is highly selective for H2O2 and hydroxyl radicals, intracellular ROS levels were also examined by another commonly used ROS probe, DHE, which is especially sensitive to superoxide. Consistently, the intracellular ROS signal-identified DHE probe was markedly increased in ARPE19 cells treated with 30 μm atRAL (Fig. 1B), a concentration that reproducibly caused excessive ARPE19 cell death as reported previously (10Maeda A. Maeda T. Golczak M. Chou S. Desai A. 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