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Serge Przedborski - One of the best experts on this subject based on the ideXlab platform.
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nadph oxidase mediates oxidative stress in the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine model of parkinson s disease
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Du Chu Wu, Kim Tieu, Peter Teismann, Vernice Jacksonlewis, Miquel Vila, Harry Ischiropoulos, Serge PrzedborskiAbstract:Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.
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bax ablation prevents dopaminergic neurodegeneration in the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mouse model of parkinson s disease
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Miquel Vila, Vernice Jacksonlewis, Gabriel Liberatore, Slobodanka Vukosavic, Ruth Djaldetti, Daniel Offen, Stanley J Korsmeyer, Serge PrzedborskiAbstract:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the pro-apoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease.
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inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of parkinson disease
Nature Medicine, 1999Co-Authors: Gabriel Liberatore, Vernice Jacksonlewis, Miquel Vila, Valina L Dawson, Ted M Dawson, Slobodanka Vukosavic, Allen S Mandir, W G Mcauliffe, Serge PrzedborskiAbstract:MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.
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role of neuronal nitric oxide in 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine MPTP induced dopaminergic neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Serge Przedborski, Vernice Jacksonlewis, Rina Yokoyama, Toshihiro Shibata, Valina L Dawson, Ted M DawsonAbstract:Abstract 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.
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time course and morphology of dopaminergic neuronal death caused by the neurotoxin 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine
Neurodegeneration, 1995Co-Authors: Vernice Jacksonlewis, Michael W Jakowec, Robert E Burke, Serge PrzedborskiAbstract:Mechanisms responsible for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine (DA) neuronal death remain unknown and in mice it is even unclear whether neuronal death does occur. In vitro studies suggest that 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP, kills neurons by apoptosis. Herein, we investigated whether MPTP induces DA neuronal death in vivo in mice and whether the mechanism is that of apoptosis. C57/bl Mice received different doses of MPTP administered in four intraperitoneal injections every 2 hours and were sacrificed at different time points for analyses of tyrosine hydroxylase (TH) immunohistochemistry, silver staining, and Nissl staining within the mesencephalon. We found that MPTP induces neuronal destruction in the substantia nigra pars compacta (SNpc) and the ventral tegmental area (VTA). The active phase of degeneration began at 12 h postinjection and continued up to 4 days. During this period, there was a greater decrease in TH-defined neurons than in Nissl-stained neurons suggesting that MPTP can cause a loss in TH without necessarily destroying the neuron. Thereafter, neuronal counts by both techniques equalized and there was no further loss of DA neurons. Dying neurons showed shrunken eosinophilic cytoplasm and shrunken darkly stained nuclei. Double staining revealed degenerating neurons solely among TH positive neurons of SNpc and VTA. At no time point and at no dose of MPTP was apoptosis observed. In addition, in situ labelling revealed no evidence of DNA fragmentation. This study demonstrates that the MPTP mouse model replicates several key features of neurodegeneration of DA neurons in PD and provides no in vivo evidence that, using this specific paradigm of injection, MPTP kills DA neurons by apoptosis.
Donato A Di Monte - One of the best experts on this subject based on the ideXlab platform.
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inhibition of monoamine oxidase contributes to the protective effect of 7 nitroindazole against MPTP neurotoxicity
Journal of Neurochemistry, 2002Co-Authors: Donato A Di Monte, Kay Castagnoli, Andrea H Anderson, Neal Castagnoli, Joyce E. Royland, William J. LangstonAbstract:Abstract: The ability of 7-nitroindazole (7-NI) to protect against MPTP-induced neurotoxicity has been attributed to its inhibition of neuronal nitric oxide synthase. In the present study, 7-NI was found to counteract almost completely striatal dopamine depletion caused by a single subcutaneus injection of 20 mg/kg MPTP in mice. This effect, however, was accompanied by a significant reduction in the striatal levels of MPP+, the toxic metabolite generated via monoamine oxidase B-catalyzed MPTP oxidation. In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP+ concentrations similar to those measured after treatment with 20 mg/kg MPTP alone. A comparison of neurotoxicity in these two experimental conditions (i.e., mice treated with 20 mg/kg alone versus 40 mg/kg MPTP plus 7-NI) revealed only a slight (20%), but statistically significant, protection of dopamine depletion with 7-NI. These data indicate that the mechanism by which 7-NI counteracts MPTP neurotoxicity in mice is not due solely to inhibition of neuronal nitric oxide synthase, but involves a reduction in MPP+ formation.
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7 nitroindazole prevents 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine induced atp loss in the mouse striatum
Brain Research, 1999Co-Authors: Donato A Di Monte, Joyce E. Royland, William J. Langston, Kioumars Delfani, Ann Marie JansonAbstract:Abstract The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP + ) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N G -nitro- l -arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.
Clifford W Shults - One of the best experts on this subject based on the ideXlab platform.
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coenzyme q10 attenuates the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine MPTP induced loss of striatal dopamine and dopaminergic axons in aged mice
Brain Research, 1998Co-Authors: Flint M Beal, Russell T Matthews, Alide Tieleman, Clifford W ShultsAbstract:Abstract We investigated whether oral administration of coenzyme Q10 (CoQ10) could attenuate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in one-year-old mice. Four groups of one-year-old, male C57BL/6 mice received a either standard diet or a diet supplemented with CoQ10 (200 mg/kg/day) for five weeks. After four weeks, one group that had received the standard diet and one group that had received the CoQ10 supplemented diet were treated with MPTP. The four groups continued on their assigned diets for an additional week prior to sacrifice. Striatal dopamine concentrations were reduced in both groups treated with MPTP, but they were significantly higher (37%) in the group treated with CoQ10 and MPTP than in the group treated with MPTP alone. The density of tyrosine hydroxylase immunoreactive (TH–IR) fibers in the caudal striatum was reduced in both MPTP-treated groups, but the density of TH–IR fibers was significantly (62%) greater in the group treated with CoQ10 and MPTP than in the group treated with MPTP alone. Our results indicate that CoQ10 can attenuate the MPTP-induced loss of striatal dopamine and dopaminergic axons in aged mice and suggest that CoQ10 may be useful in the treatment of Parkinson's disease.
Vernice Jacksonlewis - One of the best experts on this subject based on the ideXlab platform.
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ablation of the inflammatory enzyme myeloperoxidase mitigates features of parkinson s disease in mice
The Journal of Neuroscience, 2005Co-Authors: Dongkug Choi, Subramaniam Pennathur, Celine Perier, Kim Tieu, Peter Teismann, Du Chu Wu, Vernice Jacksonlewis, Miquel Vila, Jeanpaul G Vonsattel, Jay W HeineckeAbstract:Parkinson's disease (PD) is characterized by a loss of ventral midbrain dopaminergic neurons, which can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Inflammatory oxidants have emerged as key contributors to PD- and MPTP-related neurodegeneration. Here, we show that myeloperoxidase (MPO), a key oxidant-producing enzyme during inflammation, is upregulated in the ventral midbrain of human PD and MPTP mice. We also show that ventral midbrain dopaminergic neurons of mutant mice deficient in MPO are more resistant to MPTP-induced cytotoxicity than their wild-type littermates. Supporting the oxidative damaging role of MPO in this PD model are the demonstrations that MPO-specific biomarkers 3-chlorotyrosine and hypochlorous acid-modified proteins increase in the brains of MPTP-injected mice. This study demonstrates that MPO participates in the MPTP neurotoxic process and suggests that inhibitors of MPO may provide a protective benefit in PD.
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nadph oxidase mediates oxidative stress in the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine model of parkinson s disease
Proceedings of the National Academy of Sciences of the United States of America, 2003Co-Authors: Du Chu Wu, Kim Tieu, Peter Teismann, Vernice Jacksonlewis, Miquel Vila, Harry Ischiropoulos, Serge PrzedborskiAbstract:Parkinson's disease (PD) is a neurodegenerative disorder of uncertain pathogenesis characterized by a loss of substantia nigra pars compacta (SNpc) dopaminergic (DA) neurons, and can be modeled by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both inflammatory processes and oxidative stress may contribute to MPTP- and PD-related neurodegeneration. However, whether inflammation may cause oxidative damage in MPTP and PD is unknown. Here we show that NADPH-oxidase, the main reactive oxygen species (ROS)-producing enzyme during inflammation, is up-regulated in SNpc of human PD and MPTP mice. These changes coincide with the local production of ROS, microglial activation, and DA neuronal loss seen after MPTP injections. Mutant mice defective in NADPH-oxidase exhibit less SNpc DA neuronal loss and protein oxidation than their WT littermates after MPTP injections. We show that extracellular ROS are a main determinant in inflammation-mediated DA neurotoxicity in the MPTP model of PD. This study supports a critical role for NADPH-oxidase in the pathogenesis of PD and suggests that targeting this enzyme or enhancing extracellular antioxidants may provide novel therapies for PD.
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bax ablation prevents dopaminergic neurodegeneration in the 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine mouse model of parkinson s disease
Proceedings of the National Academy of Sciences of the United States of America, 2001Co-Authors: Miquel Vila, Vernice Jacksonlewis, Gabriel Liberatore, Slobodanka Vukosavic, Ruth Djaldetti, Daniel Offen, Stanley J Korsmeyer, Serge PrzedborskiAbstract:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) damages dopaminergic neurons in the substantia nigra pars compacta (SNpc) as seen in Parkinson's disease. Here, we show that the pro-apoptotic protein Bax is highly expressed in the SNpc and that its ablation attenuates SNpc developmental neuronal apoptosis. In adult mice, there is an up-regulation of Bax in the SNpc after MPTP administration and a decrease in Bcl-2. These changes parallel MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking Bax are significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that Bax plays a critical role in the MPTP neurotoxic process and suggests that targeting Bax may provide protective benefit in the treatment of Parkinson's disease.
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inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of parkinson disease
Nature Medicine, 1999Co-Authors: Gabriel Liberatore, Vernice Jacksonlewis, Miquel Vila, Valina L Dawson, Ted M Dawson, Slobodanka Vukosavic, Allen S Mandir, W G Mcauliffe, Serge PrzedborskiAbstract:MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) damages dopaminergic neurons as seen in Parkinson disease. Here we show that after administration of MPTP to mice, there was a robust gliosis in the substantia nigra pars compacta associated with significant upregulation of inducible nitric oxide synthase (iNOS). These changes preceded or paralleled MPTP-induced dopaminergic neurodegeneration. We also show that mutant mice lacking the iNOS gene were significantly more resistant to MPTP than their wild-type littermates. This study demonstrates that iNOS is important in the MPTP neurotoxic process and indicates that inhibitors of iNOS may provide protective benefit in the treatment of Parkinson disease.
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role of neuronal nitric oxide in 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine MPTP induced dopaminergic neurotoxicity
Proceedings of the National Academy of Sciences of the United States of America, 1996Co-Authors: Serge Przedborski, Vernice Jacksonlewis, Rina Yokoyama, Toshihiro Shibata, Valina L Dawson, Ted M DawsonAbstract:Abstract 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic pathway damage similar to that observed in Parkinson disease (PD). To study the role of NO radical in MPTP-induced neurotoxicity, we injected MPTP into mice in which nitric oxide synthase (NOS) was inhibited by 7-nitroindazole (7-NI) in a time- and dose-dependent fashion. 7-NI dramatically protected MPTP-injected mice against indices of severe injury to the nigrostriatal dopaminergic pathway, including reduction in striatal dopamine contents, decreases in numbers of nigral tyrosine hydroxylase-positive neurons, and numerous silver-stained degenerating nigral neurons. The resistance of 7-NI-injected mice to MPTP is not due to alterations in striatal pharmacokinetics or content of 1-methyl-4-phenylpyridinium ion (MPP+), the active metabolite of MPTP. To study specifically the role of neuronal NOS (nNOS), MPTP was administered to mutant mice lacking the nNOS gene. Mutant mice are significantly more resistant to MPTP-induced neurotoxicity compared with wild-type littermates. These results indicate that neuronally derived NO mediates, in part, MPTP-induced neurotoxicity. The similarity between the MPTP model and PD raises the possibility that NO may play a significant role in the etiology of PD.
Joyce E. Royland - One of the best experts on this subject based on the ideXlab platform.
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inhibition of monoamine oxidase contributes to the protective effect of 7 nitroindazole against MPTP neurotoxicity
Journal of Neurochemistry, 2002Co-Authors: Donato A Di Monte, Kay Castagnoli, Andrea H Anderson, Neal Castagnoli, Joyce E. Royland, William J. LangstonAbstract:Abstract: The ability of 7-nitroindazole (7-NI) to protect against MPTP-induced neurotoxicity has been attributed to its inhibition of neuronal nitric oxide synthase. In the present study, 7-NI was found to counteract almost completely striatal dopamine depletion caused by a single subcutaneus injection of 20 mg/kg MPTP in mice. This effect, however, was accompanied by a significant reduction in the striatal levels of MPP+, the toxic metabolite generated via monoamine oxidase B-catalyzed MPTP oxidation. In the presence of 7-NI, a dose of 40 mg/kg MPTP produced MPP+ concentrations similar to those measured after treatment with 20 mg/kg MPTP alone. A comparison of neurotoxicity in these two experimental conditions (i.e., mice treated with 20 mg/kg alone versus 40 mg/kg MPTP plus 7-NI) revealed only a slight (20%), but statistically significant, protection of dopamine depletion with 7-NI. These data indicate that the mechanism by which 7-NI counteracts MPTP neurotoxicity in mice is not due solely to inhibition of neuronal nitric oxide synthase, but involves a reduction in MPP+ formation.
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7 nitroindazole prevents 1 methyl 4 phenyl 1 2 3 6 tetrahydropyridine induced atp loss in the mouse striatum
Brain Research, 1999Co-Authors: Donato A Di Monte, Joyce E. Royland, William J. Langston, Kioumars Delfani, Ann Marie JansonAbstract:Abstract The neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is dependent upon the MAO-B (monoamine oxidase type B)-catalyzed production of 1-methyl-4-phenylpyridinium ion (MPP + ) and is likely to involve a perturbation of energy metabolism. Protection against MPTP neurotoxicity has been shown by treating mice with 7-nitroindazole (7-NI), a reversible inhibitor of both MAO-B and neuronal nitric oxide synthase (nNOS) activity. The objective of the present study was to evaluate (i) the relationship between the neuroprotective effect of 7-NI and MPTP-induced energy deficiency, and (ii) the role of nitric oxide production as a potential mechanism for energy perturbation after MPTP exposure. Maximum protection against striatal dopamine depletion and nigral neuronal loss was achieved when 7-NI (50 mg/kg, i.p.) was administered to C57BL/6 mice immediately before and after MPTP (50 mg/kg, s.c.). This short-term regimen of 7-NI administration parallels the time when MPTP exposure causes energy failure. 7-NI also completely prevented the loss of striatal ATP that occurs in mice during the initial hours after MPTP administration. In contrast, N G -nitro- l -arginine (two injections of 50 mg/kg each, given i.p. 20 and 4 h prior to MPTP), another NOS inhibitor, failed to affect MPTP-induced ATP depletion. Taken together, data indicate that (i) a temporal and causal relationship exists between the neuroprotective effect of 7-NI and its ability to counteract ATP reduction, and (ii) MAO-B rather than NOS inhibition is the mechanism by which 7-NI counteracts MPTP-induced ATP depletion.