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Stimulation of reactive oxygen species production by an antidepressant visible light source
BRIEF REPORT Stimulation of Reactive Oxygen Species Production by an Antidepressant Visible Light Source Dan A. Oren, Dennis S. Charney, Ronit Lavie, Michael Sinyakov, and Rachel Lubart Background: The mechanism by which visible light stimulates chronobiological phase-shifting or antidepressant effects in humans is unknown. Methods: Normal human NIH/3T3 nonpigmented fibroblasts were irradiated with a visible light source (SunRay) used in the treatment of winter seasonal depression. Electron spin resonance was assessed before and after 10 min of illumination at 2 mW/cm2 (illuminance of 3700 lux), with and without the presence of 5 L of 0.0214 mg/mL vitamin C. Results: The fibroblasts showed evidence of production of reactive oxygen species after 10 min of irradiation. Conclusions: These in vitro data establish that an antidepressant source of visible light is capable of inducing the production of reactive oxygen species in skin. Such species may participate in signal transduction pathways leading to mood changes. Biol Psychiatry 2001;49: 464 – 467 © 2001 Society of Biological Psychiatry Key Words: Light, winter, depression, reactive oxygen species, light box, fibroblasts
Introduction
T
he mechanism by which visible light stimulates chronobiological phase-shifting or antidepressant effects in humans is unknown at the molecular, cellular, and organ levels (Oren and Terman 1998; Provencio et al 2000). Mammalian chronobiological phototransduction has been localized to the eye, although the hypothesis that blood-borne pigments may act as phototransducers (Oren 1996) led one group to demonstrate that phase shifting might occur when light was applied to popliteal skin (Campbell and Murphy 1998), though another group has not been able to replicate this process (Eastman et al 2000). The role of classic (rod and cone) photoreceptors in mediating circadian effects has been questioned in recent
From the Department of Psychiatry, DVA Connecticut Healthcare System and Yale School of Medicine, West Haven, Connecticut and the Department of Physics, Chemistry and Life Sciences, Bar-Ilan University, Ramat-Gan, Israel. Address reprint requests to Dan A. Oren, M.D., VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven CT 06516. Received June 15, 2000; revised November 6, 2000; accepted November 22, 2000.
© 2001 Society of Biological Psychiatry
years (Czeisler et al 1995; Ruberg et al 1996) and remains a subject of vigorous debate. Recent data proving a role for cryptochromes in the mammalian biological clock have also been used to suggest that these blue light-sensitive molecules may be chronobiological photoreceptors, though strong arguments and data to the contrary have also been put forth (Okamura et al 1999). With regard to the well-established antidepressant effects of light in humans (Rosenthal et al 1984), there is no unequivocal explanation of the mechanism, but the prevailing concept is that this effect is mediated through the eyes (Wehr et al 1987). Some physiologic studies have reported normal visual transduction in patients with winter depression (Oren et al 1993), whereas others have reported abnormal electrophysiologic measures of visual phototransduction (Terman and Terman 1999). Recently it has been realized that visible light is capable of reactive oxygen species (ROS) production in various biological tissues (Callaghan et al 1996; Cohen et al 1998). Although high concentrations of ROS cause cell death (by adenosine triphosphate depletion and lipid peroxidation), relatively controlled concentrations of ROS stimulate signal transduction processes for transcription factor activation, gene expression, muscle contraction, and cell growth (Aitkin et al 1995; Murrell et al 1990; Suzuki and Ford 1999). Ligand-mediated signal transduction can also be blocked by antioxidants (Suzuki and Ford 1999). Production of ROS, particularly by phagocytosing cells, is known to maintain antibacterial systems of the body and may also mediate inflammation (Bagiolini and Wyman 1990; Sbarra and Strauss 1998). Given the increasingly understood role of oxy radicals as neurotransmitters and signaling molecules (Briviba et al 1997), the demonstration that visible light, as used in treatment of winter depression or shifting circadian rhythms, produces such molecules would add impetus to the hypothesis that novel mechanisms of phototransduction should be considered as potential mechanisms for these critical physiologic effects. In this study we used an electron spin resonance (ESR) technique to prove ROS production in fibroblasts irradiated by a traditional antidepressant nonlaser visible light source. 0006-3223/01/$20.00 PII S0006-3223(00)01106-9
ROS from Light
BIOL PSYCHIATRY 2001;49:464 – 467
465
Methods and Materials
Results
Irradiation
The ESR spectra of DMPO-OH (a quartet that monitors the existence of hydroxyl radicals [Buettner 1987]) before and after 10 min of illumination are depicted in Figures 1A and 1B. Figure 1A shows baseline ESR activity (background noise). Figure 1B depicts the quartet indicative of hydroxyl radicals. Irradiating the cells in the presence of vitamin C suppressed the quartet (Figure 1C), as evidence of antioxidant quenching of the generated radicals. Each figure part depicts the result of a typical experiment.
The light source was a SunRay (SunBox Company, Gaithersburg, MD) with Sylvania F032T8/750 bulbs emitting a broad band of visible light from 420 to 700 nm with sharp peaks at 435, 545, and 610 nm through a PS-49 clear acrylic methyl macrylate filter (Plastic Specialties, Hutchison, MN). This is a typical device used successfully to treat winter seasonal depression. The lamp was placed 2 cm from the center of the cell cultures, producing a power density of 2 mW/cm2 (3700 lux) at the cells’ surfaces. The cell culture was not covered during irradiation. Electron spin resonance assay was assessed before and after 10 min of illumination, with and without the presence of 5 L of 0.0214 mg/mL vitamin C. This amount of light exposure (37,000 lux-min) represents about one tenth of the typical light exposure of patients receiving therapeutic light treatment for winter depression (Rosenthal and Oren 1996). The fluorescent light source produced no detectable heat at the 2-cm distance. Since the measured energy produced by the unit was 1–2 J/cm2, an energy dose that is at least threefold below known lethal energy doses for cultured fibroblasts (Lubart et al 1992), we expected no cell destruction during treatment and did not monitor cell viability during the procedure.
Cell Line An NIH/3T3 fibroblastic (nonpigmented) cell line was used. The cells were grown in Dulbecco’s modified Eagle’s medium with 4.5g/L D-glucose and 2 mmol/L L-glutamine. The medium was supplemented with 10% newborn calf serum. During irradiation the cells were kept in phosphate-buffered saline to prevent the possibility of chromophores in the medium during irradiation.
ESR Measurements Reactive oxygen species have a very short half-life (nsec–msec), making them very difficult to detect directly. By addition of a diamagnetic compound, a spin trap that bounds the ROS, a long-lived free radical called the spin adduct is produced and can be detected by the ESR technique (Buettner 1987). We used 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) for trapping hydroxyl radicals. DMPO (0.02 mol/L) was added to 106–107 cells/mL, and 100 L of the cell culture was drawn by syringe into a gas-permeable Teflon capillary (Zeus Industries, Raritan, NJ) of 0.032-in inner diameter, 0.015-in wall thickness, and 15-cm length. Each capillary was folded twice, inserted into a narrow quartz tube that was open at both ends, and then placed into the ESR cavity. The ESR spectra were recorded on a Bruker ER 100d X-band spectrometer, before or after 10 min illumination with the light source and again following irradiation of the cells in the presence of vitamin C, a known quencher of free radicals. The measurements were repeated at least four times for each sample. The microwave of the ESR was set at 9.67 GHz and the power at 20 mW. Modulation frequency and modulation amplitude were 100 kHz and 1 G, respectively; sweep width was 65 G. Time constant was 655 msec and measurement time was 168 sec.
Discussion Irradiation of fibroblasts by visible SunBox light shows distinct evidence of hydroxyl radical production that was suppressed by the antioxidant vitamin C. These in vitro data imply the formation of ROS in the skin during the antidepressant treatment of patients with visible light therapy. Such nonvisual processes of energy transduction have also been proposed to occur in the retina (Oren 1996) but were not directly tested in this study. To the best of our knowledge no one proposes that retinal mechanisms of sight directly involve ROS formation. It has long been assumed that visible light cannot interact with nonpigmented and nonstained tissue. For the last 20 years, however, low-energy lasers and nonlaser devices in the visible spectral range have been used in medicine for treating a range of conditions including soft tissue injuries, severe wounds, and chronic pain (Baxter 1994). To interact with the living cell, light must be absorbed by chromophores in the cell. Cytochromes and endogenous porphyrins have been found to be targets of visible light (Friedmann et al 1991; Karu 1988). As a result of photoexcitation, there is an increase in ROS formation, either by enhanced redox activity of the respiratory chain due to enhancement of electron transfer or by a photodynamic action through photosensitization (Briviba et al 1997). It is well known that high amounts of ROS are lethal to cells, and recently it has been found that low amounts of ROS stimulate cell activation. Mammalian cells exist in a constant oxidative siege, requiring an appropriate balance of oxidants and antioxidants; inducement of either can modulate biological processes. For example, visible light–induced ROS alter DNA synthesis in the hemopoietic cell line U937 (Callaghan et al 1996), and in mice superoxide anion induces sperm hyperactivation and improvement in its fertilizing capability (Cohen et al 1998). As the molecular and cellular photoreceptive mechanisms by which light induces changes in mood, energy, and circadian rhythms in humans are unknown, the relationship of the data presented here to such mechanisms is speculative. Nonetheless, the increasing knowl-
466
D.A. Oren et al
BIOL PSYCHIATRY 2001;49:464 – 467
Figure 1. Electron spin resonance spectra of skin cells, with intensity expressed in arbitrary units. (A) Before irradiation. (B) After 10 min of irradiation. The quartet monitoring the 5,5-dimethyl-1-pyrroline-N-oxide-OH spin adduct demonstrates the existence of hydroxyl radicals in the cells. (C) After 10 min of irradiation in the presence of vitamin C the quartet disappears, showing that no radicals are formed. The doublet is formed by vitamin C (Goldman et al 1999).
edge base suggesting the beneficial roles of oxy radicals in human health and the demonstration that commonly used light boxes produce such effects urge that serious consideration be paid to the possibility that stimulation of ROS production is involved in such processes. Supported by a Career Development Award from the U.S. Department of Veterans Affairs (DAO).
References Aitkin RJ, Paterson M, Fisher H, Buckingham DW, Van Duim M (1995): Redox regulation of tyrosine phosphorylation in human spermatozoa and its role in the control of human sperm function. J Cell Sci 108:2017–2025. Bagiolini M, Wyman MP (1990): Turning on the respiratory burst. TIBS 15:69 –72. Baxter GD (1994): Therapeutic Lasers: Theory and Practice. Edinburgh: Churchill Livingstone.
ROS from Light
Briviba K, Klotz L-O, Sies H (1997): Toxic and signaling effects of photochemically or chemically generated singlet oxygen in biological systems. Biol Chem 378:1259 –1265. Buettner GR (1987): Spin trapping: ESR parameters of spin adducts. Free Radic Biol Med 3:259 –303. Callaghan GA, Riordan C, Gilmore WS, McIntyre IA, Allen JM, Hannigan BM (1996): Reactive oxygen species inducible by low-intensity laser irradiation alter DNA synthesis in the haemopoietic cell line U937. Lasers Surg Med 19:201–206. Campbell SS, Murphy PJ (1998): Extraocular circadian phototransduction in humans. Science 279:396 –399. Cohen N, Lubart R, Rubinstein S, Breitbart H (1998): Light irradiation of mouse spermatozoa: Stimulation of in vitro fertilization and calcium signals. Photochem Photobiol 68: 407– 413. Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman DJ, Emens JS, et al (1995): Suppression of melatonin secretion in some blind patients by exposure to light. N Engl J Med 332:6 –11. Eastman CI, Martin SK, He´bert M (2000): Failure of extraocular light to facilitate circadian rhythm reentrainment in humans. Chronobiol Int 17:807– 826. Friedmann H, Lubart R, Laulicht I (1991): A possible explanation of laser-induced stimulation. J Photochem Photobiol B 11:87–95. Goldman R, Sweetland GH, Sedlov AV, Tyurin VA, Kisin ER, Tyurina YY, et al (1999): Myeloperoxidase-catalyzed redoxcycling of phenol promotes lipid peroxidation and thiol oxidation in HL-60 cells. Free Radic Biol Med 27:1050 – 1063. Karu T (1988): The Science of Low-Power Laser Therapy. Amsterdam: Gordon and Breach. Lubart R, Wollman Y, Friedman H, Rochkind S, Laulicht I (1992): Effects of visible and near-infrared lasers on cell cultures. J Photochem Photobiol B 12:305–310. Murrell GA, Francis MJ, Bromely L (1990): Modulation of fibroblast proliferation by oxygen and free radicals. Biochem J 265:659 – 665.
BIOL PSYCHIATRY 2001;49:464 – 467
467
Okamura H, Miyake S, Sumi Y, Yamaguchi S, Yasui A, Muitjens M, et al (1999): Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 286:2531–2534. Oren DA (1996): Humoral phototransduction: Blood is a messenger. Neuroscientist 2:207–210. Oren DA, Moul DE, Schwartz PJ, Alexander JR, Yamada EM, Rosenthal NE (1993): An investigation of ophthalmic function in winter seasonal affective disorder. Depression 1:29 – 37. Oren DA, Terman M (1998): Tweaking the human circadian clock with light. Science 279:333–334. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD (2000): A novel human opsin in the inner retina. J Neurosci 20:600 – 605. Rosenthal NE, Oren DA (1996): Light therapy. In: Gabbard GO, Atkinson SD, editors. Synopsis of Treatments of Psychiatric Disorders, 2nd ed. Washington, DC: American Psychiatric Press, 543–546. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, et al (1984): Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:72– 80. Ruberg FL, Skene DJ, Hanifin JP, Rollag MD, English J, Arendt J, et al (1996): Melatonin regulation in humans with color vision deficiencies. J Clin Endocrinol Metab 81:2980 –2985. Sbarra AJ, Strauss RR (1998): The Respiratory Burst and Its Photobiological Significance. New York: Plenum Press. Suzuki YJ, Ford GD (1999): Redox regulation of signal transduction in cardiac and smooth muscle. J Mol Cell Cardiol 31:345–353. Terman JS, Terman M (1999): Photopic and scotopic light detection in patients with seasonal affective disorder and control subjects. Biol Psychiatry 46:1642–1648. Wehr TA, Skwerer RG, Jacobsen FM, Sack DA, Rosenthal NE (1987): Eye versus skin phototherapy of seasonal affective disorder. Am J Psychiatry 144:753–757.
Introduction
T
he mechanism by which visible light stimulates chronobiological phase-shifting or antidepressant effects in humans is unknown at the molecular, cellular, and organ levels (Oren and Terman 1998; Provencio et al 2000). Mammalian chronobiological phototransduction has been localized to the eye, although the hypothesis that blood-borne pigments may act as phototransducers (Oren 1996) led one group to demonstrate that phase shifting might occur when light was applied to popliteal skin (Campbell and Murphy 1998), though another group has not been able to replicate this process (Eastman et al 2000). The role of classic (rod and cone) photoreceptors in mediating circadian effects has been questioned in recent
From the Department of Psychiatry, DVA Connecticut Healthcare System and Yale School of Medicine, West Haven, Connecticut and the Department of Physics, Chemistry and Life Sciences, Bar-Ilan University, Ramat-Gan, Israel. Address reprint requests to Dan A. Oren, M.D., VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven CT 06516. Received June 15, 2000; revised November 6, 2000; accepted November 22, 2000.
© 2001 Society of Biological Psychiatry
years (Czeisler et al 1995; Ruberg et al 1996) and remains a subject of vigorous debate. Recent data proving a role for cryptochromes in the mammalian biological clock have also been used to suggest that these blue light-sensitive molecules may be chronobiological photoreceptors, though strong arguments and data to the contrary have also been put forth (Okamura et al 1999). With regard to the well-established antidepressant effects of light in humans (Rosenthal et al 1984), there is no unequivocal explanation of the mechanism, but the prevailing concept is that this effect is mediated through the eyes (Wehr et al 1987). Some physiologic studies have reported normal visual transduction in patients with winter depression (Oren et al 1993), whereas others have reported abnormal electrophysiologic measures of visual phototransduction (Terman and Terman 1999). Recently it has been realized that visible light is capable of reactive oxygen species (ROS) production in various biological tissues (Callaghan et al 1996; Cohen et al 1998). Although high concentrations of ROS cause cell death (by adenosine triphosphate depletion and lipid peroxidation), relatively controlled concentrations of ROS stimulate signal transduction processes for transcription factor activation, gene expression, muscle contraction, and cell growth (Aitkin et al 1995; Murrell et al 1990; Suzuki and Ford 1999). Ligand-mediated signal transduction can also be blocked by antioxidants (Suzuki and Ford 1999). Production of ROS, particularly by phagocytosing cells, is known to maintain antibacterial systems of the body and may also mediate inflammation (Bagiolini and Wyman 1990; Sbarra and Strauss 1998). Given the increasingly understood role of oxy radicals as neurotransmitters and signaling molecules (Briviba et al 1997), the demonstration that visible light, as used in treatment of winter depression or shifting circadian rhythms, produces such molecules would add impetus to the hypothesis that novel mechanisms of phototransduction should be considered as potential mechanisms for these critical physiologic effects. In this study we used an electron spin resonance (ESR) technique to prove ROS production in fibroblasts irradiated by a traditional antidepressant nonlaser visible light source. 0006-3223/01/$20.00 PII S0006-3223(00)01106-9
ROS from Light
BIOL PSYCHIATRY 2001;49:464 – 467
465
Methods and Materials
Results
Irradiation
The ESR spectra of DMPO-OH (a quartet that monitors the existence of hydroxyl radicals [Buettner 1987]) before and after 10 min of illumination are depicted in Figures 1A and 1B. Figure 1A shows baseline ESR activity (background noise). Figure 1B depicts the quartet indicative of hydroxyl radicals. Irradiating the cells in the presence of vitamin C suppressed the quartet (Figure 1C), as evidence of antioxidant quenching of the generated radicals. Each figure part depicts the result of a typical experiment.
The light source was a SunRay (SunBox Company, Gaithersburg, MD) with Sylvania F032T8/750 bulbs emitting a broad band of visible light from 420 to 700 nm with sharp peaks at 435, 545, and 610 nm through a PS-49 clear acrylic methyl macrylate filter (Plastic Specialties, Hutchison, MN). This is a typical device used successfully to treat winter seasonal depression. The lamp was placed 2 cm from the center of the cell cultures, producing a power density of 2 mW/cm2 (3700 lux) at the cells’ surfaces. The cell culture was not covered during irradiation. Electron spin resonance assay was assessed before and after 10 min of illumination, with and without the presence of 5 L of 0.0214 mg/mL vitamin C. This amount of light exposure (37,000 lux-min) represents about one tenth of the typical light exposure of patients receiving therapeutic light treatment for winter depression (Rosenthal and Oren 1996). The fluorescent light source produced no detectable heat at the 2-cm distance. Since the measured energy produced by the unit was 1–2 J/cm2, an energy dose that is at least threefold below known lethal energy doses for cultured fibroblasts (Lubart et al 1992), we expected no cell destruction during treatment and did not monitor cell viability during the procedure.
Cell Line An NIH/3T3 fibroblastic (nonpigmented) cell line was used. The cells were grown in Dulbecco’s modified Eagle’s medium with 4.5g/L D-glucose and 2 mmol/L L-glutamine. The medium was supplemented with 10% newborn calf serum. During irradiation the cells were kept in phosphate-buffered saline to prevent the possibility of chromophores in the medium during irradiation.
ESR Measurements Reactive oxygen species have a very short half-life (nsec–msec), making them very difficult to detect directly. By addition of a diamagnetic compound, a spin trap that bounds the ROS, a long-lived free radical called the spin adduct is produced and can be detected by the ESR technique (Buettner 1987). We used 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) for trapping hydroxyl radicals. DMPO (0.02 mol/L) was added to 106–107 cells/mL, and 100 L of the cell culture was drawn by syringe into a gas-permeable Teflon capillary (Zeus Industries, Raritan, NJ) of 0.032-in inner diameter, 0.015-in wall thickness, and 15-cm length. Each capillary was folded twice, inserted into a narrow quartz tube that was open at both ends, and then placed into the ESR cavity. The ESR spectra were recorded on a Bruker ER 100d X-band spectrometer, before or after 10 min illumination with the light source and again following irradiation of the cells in the presence of vitamin C, a known quencher of free radicals. The measurements were repeated at least four times for each sample. The microwave of the ESR was set at 9.67 GHz and the power at 20 mW. Modulation frequency and modulation amplitude were 100 kHz and 1 G, respectively; sweep width was 65 G. Time constant was 655 msec and measurement time was 168 sec.
Discussion Irradiation of fibroblasts by visible SunBox light shows distinct evidence of hydroxyl radical production that was suppressed by the antioxidant vitamin C. These in vitro data imply the formation of ROS in the skin during the antidepressant treatment of patients with visible light therapy. Such nonvisual processes of energy transduction have also been proposed to occur in the retina (Oren 1996) but were not directly tested in this study. To the best of our knowledge no one proposes that retinal mechanisms of sight directly involve ROS formation. It has long been assumed that visible light cannot interact with nonpigmented and nonstained tissue. For the last 20 years, however, low-energy lasers and nonlaser devices in the visible spectral range have been used in medicine for treating a range of conditions including soft tissue injuries, severe wounds, and chronic pain (Baxter 1994). To interact with the living cell, light must be absorbed by chromophores in the cell. Cytochromes and endogenous porphyrins have been found to be targets of visible light (Friedmann et al 1991; Karu 1988). As a result of photoexcitation, there is an increase in ROS formation, either by enhanced redox activity of the respiratory chain due to enhancement of electron transfer or by a photodynamic action through photosensitization (Briviba et al 1997). It is well known that high amounts of ROS are lethal to cells, and recently it has been found that low amounts of ROS stimulate cell activation. Mammalian cells exist in a constant oxidative siege, requiring an appropriate balance of oxidants and antioxidants; inducement of either can modulate biological processes. For example, visible light–induced ROS alter DNA synthesis in the hemopoietic cell line U937 (Callaghan et al 1996), and in mice superoxide anion induces sperm hyperactivation and improvement in its fertilizing capability (Cohen et al 1998). As the molecular and cellular photoreceptive mechanisms by which light induces changes in mood, energy, and circadian rhythms in humans are unknown, the relationship of the data presented here to such mechanisms is speculative. Nonetheless, the increasing knowl-
466
D.A. Oren et al
BIOL PSYCHIATRY 2001;49:464 – 467
Figure 1. Electron spin resonance spectra of skin cells, with intensity expressed in arbitrary units. (A) Before irradiation. (B) After 10 min of irradiation. The quartet monitoring the 5,5-dimethyl-1-pyrroline-N-oxide-OH spin adduct demonstrates the existence of hydroxyl radicals in the cells. (C) After 10 min of irradiation in the presence of vitamin C the quartet disappears, showing that no radicals are formed. The doublet is formed by vitamin C (Goldman et al 1999).
edge base suggesting the beneficial roles of oxy radicals in human health and the demonstration that commonly used light boxes produce such effects urge that serious consideration be paid to the possibility that stimulation of ROS production is involved in such processes. Supported by a Career Development Award from the U.S. Department of Veterans Affairs (DAO).
References Aitkin RJ, Paterson M, Fisher H, Buckingham DW, Van Duim M (1995): Redox regulation of tyrosine phosphorylation in human spermatozoa and its role in the control of human sperm function. J Cell Sci 108:2017–2025. Bagiolini M, Wyman MP (1990): Turning on the respiratory burst. TIBS 15:69 –72. Baxter GD (1994): Therapeutic Lasers: Theory and Practice. Edinburgh: Churchill Livingstone.
ROS from Light
Briviba K, Klotz L-O, Sies H (1997): Toxic and signaling effects of photochemically or chemically generated singlet oxygen in biological systems. Biol Chem 378:1259 –1265. Buettner GR (1987): Spin trapping: ESR parameters of spin adducts. Free Radic Biol Med 3:259 –303. Callaghan GA, Riordan C, Gilmore WS, McIntyre IA, Allen JM, Hannigan BM (1996): Reactive oxygen species inducible by low-intensity laser irradiation alter DNA synthesis in the haemopoietic cell line U937. Lasers Surg Med 19:201–206. Campbell SS, Murphy PJ (1998): Extraocular circadian phototransduction in humans. Science 279:396 –399. Cohen N, Lubart R, Rubinstein S, Breitbart H (1998): Light irradiation of mouse spermatozoa: Stimulation of in vitro fertilization and calcium signals. Photochem Photobiol 68: 407– 413. Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman DJ, Emens JS, et al (1995): Suppression of melatonin secretion in some blind patients by exposure to light. N Engl J Med 332:6 –11. Eastman CI, Martin SK, He´bert M (2000): Failure of extraocular light to facilitate circadian rhythm reentrainment in humans. Chronobiol Int 17:807– 826. Friedmann H, Lubart R, Laulicht I (1991): A possible explanation of laser-induced stimulation. J Photochem Photobiol B 11:87–95. Goldman R, Sweetland GH, Sedlov AV, Tyurin VA, Kisin ER, Tyurina YY, et al (1999): Myeloperoxidase-catalyzed redoxcycling of phenol promotes lipid peroxidation and thiol oxidation in HL-60 cells. Free Radic Biol Med 27:1050 – 1063. Karu T (1988): The Science of Low-Power Laser Therapy. Amsterdam: Gordon and Breach. Lubart R, Wollman Y, Friedman H, Rochkind S, Laulicht I (1992): Effects of visible and near-infrared lasers on cell cultures. J Photochem Photobiol B 12:305–310. Murrell GA, Francis MJ, Bromely L (1990): Modulation of fibroblast proliferation by oxygen and free radicals. Biochem J 265:659 – 665.
BIOL PSYCHIATRY 2001;49:464 – 467
467
Okamura H, Miyake S, Sumi Y, Yamaguchi S, Yasui A, Muitjens M, et al (1999): Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 286:2531–2534. Oren DA (1996): Humoral phototransduction: Blood is a messenger. Neuroscientist 2:207–210. Oren DA, Moul DE, Schwartz PJ, Alexander JR, Yamada EM, Rosenthal NE (1993): An investigation of ophthalmic function in winter seasonal affective disorder. Depression 1:29 – 37. Oren DA, Terman M (1998): Tweaking the human circadian clock with light. Science 279:333–334. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD (2000): A novel human opsin in the inner retina. J Neurosci 20:600 – 605. Rosenthal NE, Oren DA (1996): Light therapy. In: Gabbard GO, Atkinson SD, editors. Synopsis of Treatments of Psychiatric Disorders, 2nd ed. Washington, DC: American Psychiatric Press, 543–546. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, et al (1984): Seasonal affective disorder: A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:72– 80. Ruberg FL, Skene DJ, Hanifin JP, Rollag MD, English J, Arendt J, et al (1996): Melatonin regulation in humans with color vision deficiencies. J Clin Endocrinol Metab 81:2980 –2985. Sbarra AJ, Strauss RR (1998): The Respiratory Burst and Its Photobiological Significance. New York: Plenum Press. Suzuki YJ, Ford GD (1999): Redox regulation of signal transduction in cardiac and smooth muscle. J Mol Cell Cardiol 31:345–353. Terman JS, Terman M (1999): Photopic and scotopic light detection in patients with seasonal affective disorder and control subjects. Biol Psychiatry 46:1642–1648. Wehr TA, Skwerer RG, Jacobsen FM, Sack DA, Rosenthal NE (1987): Eye versus skin phototherapy of seasonal affective disorder. Am J Psychiatry 144:753–757.