* The University of Tsukuba, Institute of Community Medicine, Tsukuba, Ibaraki, 305-8575 Japan; and
Recipient of a Research Fellowship for Foreign Scientists on the Japan Society for the Promotion of Science
Received January 16, 2003; accepted March 17, 2003
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ABSTRACT |
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Key Words: melatonin; ganglioside GT1b; L-cysteine; mitochondrial DNA; lipid peroxidation; seizures; hydroxyl radical.
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INTRODUCTION |
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A number of reports have suggested that L-cysteine, administered to perinatal mice or rats that possess an immature blood-brain barrier, produces widespread neurodegeneration and brain atrophy of the cerebral cortex, hippocampus, thalamus, and striatum (Olney and Ho, 1970; Olney et al., 1971
). Furthermore, our previous reports showed that an intracerebroventricular (icv) injection of L-cysteine produces severe seizures in adult animals (Yamamoto, 1996
; Yamamoto and Tang, 1996a
,b
). L-cysteine activates selectively the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor, which in turn generates reactive oxygen species including the hydroxyl free radical, OH. The L-cysteineinduced lipid peroxidation in the mouse brain and is blocked by the OH scavenger, melatonin (Yamamoto and Tang, 1996a
,b
). The role that NMDA receptor plays in epilepsy, seizure-induced brain damage, and glutamate excitotoxicity is well established (Choi, 1985
; Choi et al., 1988
; Dingledine et al., 1990
).
Mitochondria generate most of the free radicals in the cell, and it has been estimated that up to 2% to 4% of the inhaled oxygen is converted to free radicals (Tully et al., 2000). Oxidative damage to mitochondrial DNA (mtDNA) may induce specific mutations, deletions, or point mutations within the mitochondrial genome (Jazin et al., 1996
). A major emphasis in the past has been on the interaction of chemical toxins with nuclear DNA; subsequently it was observed that damage to mtDNA is greater than that of nuclear DNA (Duara et al., 1993
; Edland et al., 1996
; Shigenaga et al., 1994
).
It is well documented that DNA is susceptible to OH damage. Reactive oxygen species such as OH cause damage to many biomolecules, and we have found that H2O2/Fe2+-induced destruction of DNA is a result of OH (Uz et al., 1996; Yamamoto and Mohanan, 2001b
). Recently, we have also reported that melatonin inhibits DNA damage induced by kainic acid, paraquat, and cyanide in the mouse, using both in vitro and in vivo methods (Mohanan and Yamamoto, 2002
; Yamamoto and Mohanan, 2001a
,b
, 2002
, 2003
).
Gangliosides are glycosphingolipids containing sialic acid residues. They exist in mammalian cell membrane and are particularly abundant in neuronal cell membrane (Stults et al., 1989; Wiegandt, 1995
). Gangliosides attenuate excitotoxic neuronal injury (Dawson et al., 1995
; Favaron et al., 1988
). Several mechanisms have been suggested to underlie the neuroprotective effects of gangliosides, including inhibition of protein kinase C translocation (Vaccarino et al., 1987
), inhibition of lipid peroxidation (Tyurina et al., 1990
, 1993
), inhibition of nitric oxide synthase (Dawson et al., 1995
), and phosphorylation of the nerve growth factor receptor Trk (Ferrari et al., 1995
; Rabin et al., 1995
). Favaron et al. (1988)
reported that gangliosides prevent kainate neurotoxicity in primary neuronal cultures of neonatal rat cerebellum and cortex. It has been reported that gangliosides inhibit the intensification of free radicals reactions by glutamate (Avrova et al., 1998
) and also protect polyenoic fatty acids from oxidative destruction in synaptosomes of rat brain (Tyurina et al., 1990
, 1993
). Rahmann (1987)
reported that seizure-inducing agents such as tetrazolium, bemegride, and cobalt reduce the ganglioside content in brain. Our previous reports have suggested that in vivo and in vitro exposures to cyanide cause severe seizures and damage to the brain mtDNA in mice (Monahan and Yamamoto, 2002
; Yamamoto, 1995
), and the cyanide-induced seizures are abolished by an icv injection of gangliosides (Yamamoto, 1995
). In this study, we evaluated the effects of L-cysteine on mtDNA and lipid peroxidation in the mouse brain and the neuroprotective effects of melatonin or ganglioside GT1b against those effects.
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MATERIALS AND METHODS |
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Animals.
Male ddy strain mice (4 weeks old, weight 2224 g) used in all the experiments were purchased from SLC, Inc. (Shizuoka, Japan). They were housed in groups of six mice per plastic cage, with wood shavings as bedding. They were given a diet of standard laboratory chow, supplied by Oriental Kobo Ltd. (Tokyo, Japan) and water ad libitum. All procedures were performed in accordance with approved institutional protocols, the 1996 National Research Council Guide for the Care and Use of Laboratory Animals, and the Society for Neuroscience Policy on the Use of Animals in Neuroscience Research.
Experimental design.
Thirty-six animals were divided into six experimental groups as follows: Group I, Saline only; Group II, L-cysteine (1.25 µmol/animal; 5µl/animal) plus saline (10ml/kg, injected 30 min before L-cysteine administration); Group III, L-cysteine (1.25 µmol/animal; 5 µl/animal) plus melatonin (20 mg/kg, injected 30 min before L-cysteine administration); Group IV L-cysteine (1.25 µmol/animal) plus ganglioside GT1b (90 nmol/animal, injected 1 min before L-cysteine administration); Group V, melatonin (20 mg/kg) only; Group VI, ganglioside GT1b (90 nmol/animal) only.
L-cysteine and ganglioside GT1b were injected intracerebroventrically, and melatonin was injected intraperitoneally as described by our previous report (Yamamoto, 1995; Yamamoto and Tang, 1996b
). Behavior of the treated animals was observed for 30 min after administration of L-cysteine.
Brain collection and preservation.
Thirty min after dosing, L-cysteinetreated groups, were decapitated, and their brains were immediately removed under aseptic conditions. Animals of other groups were also decapitated at the same time, and brains were collected in the same manner. The brains were cut and separated into frontal and central cortical regions with weights of approximately 100 mg each. All the brains were immediately frozen at -20°C for mtDNA isolation.
Preparation of brain homogenate.
Frozen brain regions (100 mg) were immediately homogenized with ice-cold buffer (1.0 ml) supplied with the mtDNA extractor kit (mtDNA extractor CT kit, Wako, Japan), at a speed of 1000 r.p.m. using a Potter-Elvehjems glass homogenizer (Iuchi, Tokyo, Japan) fitted with a Teflon pestle with a clearance of 0.23 mm, to prepare a 10% (w/v) brain homogenate. The brain homogenate was kept on ice, mixed uniformly, and was used for mtDNA extraction. All the procedures were carried out under sterile conditions.
Preparation of crude mitochondria fraction from brain.
The brain homogenate was uniformly mixed and after centrifugation at 1,000 x g for 1 min, the nuclei and cell debris was removed. The supernatant solution was carefully separated and was further centrifuged at 10,000 x g for 10 min at 4°C. The supernatant was discarded, and the crude mitochondrial pellet was directly subjected to mtDNA isolation without further treatment.
In vitro experiments.
One ml of 10% (w/v) homogenate of whole fresh brain was incubated with L-cysteine (0, 0.05, 0.5, or 1.0 mM) in the presence or absence of melatonin (1.5 mM) or ganglioside GT1b (60 µM) at 37°C for 60 min in a shaking water bath. After incubation, the homogenate was centrifuged at 1000 x g for 1 min at 4°C using a micro-centrifuge (Iuchi, Tokyo, Japan) and the supernatant solution was carefully separated and further centrifuged at 10,000 x g for 10 min at 4°C. The supernatant was discarded and this crude mitochondrial pellet was used for mtDNA isolation.
Isolation of brain mtDNA using mtDNA extractor CT kit (Kit containing buffer, solution I, II A & B, III, sodium iodide and washing solution).
The crude mitochondria pellet was resuspended in 50 ml of solution I and vortexed thoroughly. Further, 100 ml of solution IIA and B (equal volume of Solution II A and B) was added in the suspension and vortexed again and kept on ice for 5 min. To this solution, 75 ml of Solution III was added, slowly mixed and kept on ice for 5 min again. The aliquots were centrifuged at 12,000 x g for 5 min at 4°C, and 200 ml of the supernatant solution was transferred to another tube. Subsequently, 300 ml of sodium iodide solution and 500 ml of isopropyl alcohol were added to this solution and vortexed. The aliquots were centrifuged at 12,000 x g for 10 min at room temperature. The supernatant solution was discarded, and the pellet was resuspended in washing solution and centrifuged at 12,000 x g for 5 min (two times) at room temperature. The final mtDNA pellet was dried under vacuum and resuspended in TE buffer, pH 8.0 solution; this was used for restriction endonuclease digestion.
Restriction endonuclease digestion.
The mtDNA was completely digested with restriction endonuclease as indicated below. A total volume of 26 ml digestion mixture contained 20.4 ml of mtDNA (contains 1.0 mg of mtDNA), 2 ml of Hind II enzyme (20 units), 2.6 ml of enzyme buffer, and 1 ml of RNase (10 mg/ml). The digestions were carried out at 37°C for 2 h in a shaking water bath.
Gel electrophoresis.
Agarose (0.8%) slab gels were prepared by dissolving in 0.06 M barbital sodium solution at pH 8.6. Agarose gel electrophoresis was performed in a running TAE buffer at a voltage of 5V/cm at room temperature using a Mini-Gel Electrophoresis system (Mupid-2, Advance Co. Ltd., Tokyo, Japan). Following electrophoresis, gels were stained with ethidium bromide solution (0.5 mg/ml) for 20 min and irradiated from below with a UV transilluminator box at a wavelength 254nm and photographed through an orange filter.
Lipid peroxidation assay.
Lipid peroxidation was carried out by in vitro and in vivo methods. Lipid peroxidation of brain homogenate was determined as previously described (Yamamoto and Tang, 1996a). For in vitro studies, aliquots (1 ml) of 10% (w/v) whole brain homogenate of mice were incubated, either in a shaking water bath for 20 min at 37°C or at 0°C on ice (time zero samples), with a concentration of L-cysteine (0.05, 0.5 or 1.0 mM) in the presence or absence of melatonin (1.0 mM) or ganglioside GT1b (60 µM). Each experiment was performed on a pool of brain extracts from eight mice; three aliquots were used from each homogenate. For in vivo studies, aliquots (1 ml) of 10% (w/v) whole brain homogenate of mouse treated with saline, melatonin (20 mg/kg) only, ganglioside GT1b (90 nmol/animal) only, L-cysteine (1.25 µmol/animal) only, L-cysteine (1.25 µmol/animal) plus melatonin (20 mg/kg), or L-cysteine (1.25 µmol/animal) plus ganglioside GT1b were incubated under the same conditions mentioned above. The samples were cooled on ice for 10 min. Thereafter, the reaction was stopped and the samples were centrifuged at 10,000 x g for 15 min in a refrigerated centrifuge (Kokusan Co., Tokyo, Japan) and immediately tested for lipid peroxidation by measuring the concentration of malonaldehyde (MDA) and 4-hydroxyalkenals (4-HDA) in the tissues. Lipid peroxidation was expressed in terms of MDA + 4-HDA per mg protein. The Bioxytech LPO-586 kit was used for these measurements. Protein concentrations were determined by the method of Lowry et al.(1951)
, with bovine serum albumin as standard. All data were statistically analyzed by an analysis of variance (ANOVA). Where a significant difference was indicated, the means were determined by Student-Newman-Keuls test; p < 0.05 was considered as significant.
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RESULTS |
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DISCUSSION |
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The L-cysteine contains a thiol group which provides a special feature that may explain its neurotoxicity, and it produces reactive oxygen species such as OH. The autoxidation of thiols in the presence of iron generates reactive oxygen species (Misra, 1974; Nath and Salahudeen, 1993
; Saez et al., 1982
; Yamamoto and Mohanan, 2001b
; Yamamoto and Tang, 1996a
). A number of reports suggest that the neurotoxicity of reactive oxygen species may be based on activation of NMDA receptors by the reduction of the redox site on the NMDA receptor-ion channel complex (Goel et al., 1993
; Lipton and Stamler, 1994
); this may be via the modification of the NMDA receptor by oxidation of the SH group of proteins at the redox site (Aizemnman et al., 1990
) or by the nonvesicular basal release of aspartate (Gilman et al., 1994
), and/or by activation of non-NMDA receptors (Hall et al., 1978
; Melchiorri et al., 1995
; Mohanan and Yamamoto, 2002
). It is well known that L-cysteine activates selectively the NMDA subtype of glutamate receptor (Olney et al., 1990
) and results in a transmembrane ion imbalance, especially via induction of calcium influx. Elevation of cytosolic Ca2+ is believed to activate nitric oxide (NO) synthase, resulting in the generation of NO. Many reports suggest that NO is a mediator of cell toxicity (Beckman, 1991
; Yamamoto, 1996
; Youdim et al., 1993
). NO is a free radical which reacts with superoxide (O2-) to form peroxynitrite anions (ONOO-) (Blough and Zafiriou, 1985
). ONOO-can generate OH (Beckman, 1991
). This means that L-cysteine may produce OH by both the activation of NMDA receptors and autoxidation of thiols. In support of this hypothesis, our previous reports showed that L-cysteine and NMDA-induced neurotoxicity is prevented by NG-nitro-L-arginine, NO synthase inhibitor (Yamamoto, 1996
) or melatonin, a scavenger of OH (Yamamoto and Tang. 1998
). It is also suggested that OH attacks macromolecules within neurons, resulting in membrane lipid peroxidation and DNA strand breaks. Our results suggest that L-cysteineinduced mtDNA damage and lipid peroxidation may be due to reactive oxygen species including OH. Hence, the mtDNA damage and increased lipid peroxidation induced by L-cysteine were completely inhibited by in vivo and in vitro exposure of the reactive oxygen species scavenger, melatonin or ganglioside GT1b.
Since it is known that cyclic AMP attenuates reactive oxygen species-mediated neuron toxicity (Keller et al., 1998) and ganglioside GT1b inhibits cyclic AMP-dependent protein kinase (Yates et al., 1989
), a part of preventive effect of ganglioside GT1b against L-cysteineinduced brain mtDNA damage may be due to its inhibition of cyclic AMP dependent pathway in mouse brain, however, further studies may be necessary to elucidate this hypothesis.
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ACKNOWLEDGMENTS |
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NOTES |
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