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1.
Effects of a unilateral stereotaxic injection of Tinuvin 123 into the substantia nigra on the nigrostriatal dopaminergic pathway in the rat 总被引:1,自引:0,他引:1
Tinuvin 123, a compound used in the manufacture of plastics, has recently been suggested to possibly cause Parkinson's disease (PD). Herein, we revisited this issue by assessing the effect of Tinuvin 123 on dopaminergic neurons of the substantia nigra following its stereotaxic injection in the rat. Twenty-one days post unilateral stereotaxic injection of Tinuvin 123, systemic injection of both apomorphine and amphetamine caused rotations toward the side of the lesion in these rats. Tinuvin 123 produced a small to moderate dose-dependent reduction in striatal levels of dopamine and metabolites on the side of the lesion. This compound also produced dramatic cell loss in the substantia nigra on the side of the lesion. However, the loss of cells lacked the phenotypic specificity for tyrosine hydroxylase (TH)-positive neurons that is expected with a dopaminergic neurotoxin. Indeed, aside from a robust glial reaction, both TH-positive and glutamic acid dehydrogenase (GAD)-positive neurons were destroyed, and near the site of the injection, there was complete tissue destruction. This study indicates that, using this mode of injection, Tinuvin 123 exerts a dramatic tissue toxicity without any evidence of specificity for dopaminergic neurons. Thus, our data argues against a role for Tinuvin 123 as an environmental toxin causing a clinical condition characterized by the selective loss of dopaminergic neurons as seen in PD. 相似文献
2.
Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease 总被引:6,自引:0,他引:6
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Smith PD Crocker SJ Jackson-Lewis V Jordan-Sciutto KL Hayley S Mount MP O'Hare MJ Callaghan S Slack RS Przedborski S Anisman H Park DS 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(23):13650-13655
Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease. 相似文献
3.
NADPH oxidase mediates oxidative stress in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease 总被引:22,自引:0,他引:22
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Wu DC Teismann P Tieu K Vila M Jackson-Lewis V Ischiropoulos H Przedborski S 《Proceedings of the National Academy of Sciences of the United States of America》2003,100(10):6145-6150
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. 相似文献
4.
Wu DC Tieu K Cohen O Choi DK Vila M Jackson-Lewis V Teismann P Przedborski S 《Journal of neurovirology》2002,8(6):551-558
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). The loss of these neurons is associated with a glial response composed mainly of activated microglial cells and, to a lesser extent, of reactive astrocytes. This glial response may be the source of trophic factors and can protect against reactive oxygen species and glutamate. Alternatively, this glial response can also mediate a variety of deleterious events related to the production of pro-oxidant reactive species, proinflammatory prostaglandin, and cytokines. In this review, the authors discuss the potential protective and deleterious effects of glial cells in the SNpc of PD and examine how these factors may contribute to the pathogenesis of this disease. 相似文献
5.
Rats with experimentally induced DA deficiency were treated with intracerebroventricular administration of (+)-4-propyl-9-hydroxynaphthoxacine (PHNO) through a totally implanted chronic delivery system which delivered PHNO, 0.9 microgram/h, continuously for up to 2 weeks. Rats with 6-OH-DA induced unilateral nigrostriatal lesion showed, after PHNO infusion, a potent and persistent contralateral turning behavior (8-11 turns/min) which was not present in vehicle-infused animals. The intensity of spontaneous and apomorphine-induced rotation did not decrease after 2 weeks of continuous infusion, suggesting that tolerance to PHNO or to other dopamine agonists did not develop. The magnitude of the spontaneous turning behavior in PHNO-infused animals correlated well with the baseline response to apomorphine (r = 0.505, p less than 0.025). Rats implanted with pumps delivering PHNO or vehicle were treated with reserpine, 0.5 mg/kg/day for 14 days. Vehicle-infused, reserpinized animals had a severe akinesia and weight loss during the experimental period (motor activity, measured in counts per minute was reduced to 5-10% of baseline levels, and body weight to 50% of baseline levels). PHNO-infusion partially restored activity to 60% of baseline counts and reduced the severity of weight loss. PHNO effects were observed for as long as the infusion was maintained. No side effects were observed. Intracerebroventricular infusion of PHNO may be an alternative experimental approach to untreatable motor fluctuations in Parkinson's disease. 相似文献
6.
7.
Regional effects of 6-hydroxydopamine (6-OHDA) on free radical scavengers in rat brain 总被引:2,自引:0,他引:2
A S Perumal W K Tordzro M Katz V Jackson-Lewis T B Cooper S Fahn J L Cadet 《Brain research》1989,504(1):139-141
Superoxide dismutase (SOD), catalase, glutathione (GSH), and glutathione peroxidase (GSH-Px) were measured in the caudate-putamen (CPu), the hippocampus (HIP), and the brainstem (BS) of the brains of control animals and of rats treated with one intracerebroventricular infusion of 6-hydroxydopamine (6-OHDA). Injection of 6-OHDA resulted in significant decreases in the activity of SOD in the CPu, the BS, and in the HIP. There were decreases in catalase in the CPu and in the BS, but not in the HIP. GSH was reduced in the CPu and the BS but not changed in the HIP. There were small decreases in the activity of GSH-Px only in the BS. These changes may be secondary to the production of free radicals after the infusion of 6-OHDA in rat brain. 相似文献
8.
9.
Stuart R. Snider Carl Miller A. L. N. Prasad Vernice Jackson Stanley Fahn 《Naunyn-Schmiedeberg's archives of pharmacology》1977,297(1):17-22
Summary Dopamine (DA) concentrations in rat adrenals, plasma and brain were variably elevated 1 h after a large parenteral dose of morphine. In adrenals, unlabelled DA increased 2-fold and labelled DA, synthesized from 3H-tyrosine, increased more than 4-fold. The increases could be prevented by inhibition of DA-synthesizing enzymes and spinal cord transection, respectively. Labelled DA in plasma increased 2.7-fold after morphine in intact rats but did not increase in those with spinal cord transection.It is concluded that: (1) morphine stimulates the adrenal by increasing nerve impulse flow, (2) increased nerve impulse flow increases DA synthesis and levels, and (3) the increased DA levels result in increased release of DA into the bloodstream.A preliminary account of this work was presented at the American Society of Biological Chemists, San Francisco, June 6–10, 1976 (Prasad et al., 1976) 相似文献
10.