Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the present study, we evaluated the effect of melatonin, a well-known free radical scavenger and neuroprotector, against rotenone-induced oxidative stress in a hemiparkinsonian rat model. The effect of melatonin on glutathione (GSH) depletion caused by unilateral, intranigral infusion of rotenone was investigated employing a spectrofluorimetric procedure. We also studied the effect of melatonin on rotenone-induced changes in the antioxidant enzymes superoxide dismutase (SOD) and catalase in the cytosolic fractions of substantia nigra (SN), employing spectrophotometric procedures. Rotenone-induced hydroxyl radicals (*OH) in the isolated mitochondria, as measured employing a sensitive HPLC-electrochemical method, were significantly scavenged by melatonin. Melatonin treatment restored the rotenone-induced decrease in GSH level and changes in antioxidant enzyme (SOD and catalase) activities in the SN. Our results strongly indicate melatonin's beneficial use in Parkinson's disease therapy as an antioxidant.
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PMID:Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. 1734 22

Exposure to environmental toxins increases the risk of neurodegenerative diseases including Parkinson's disease (PD). Rotenone is a neurotoxin that has been used to induce experimental Parkinsonism in rats. We used the rotenone model of experimental Parkinsonism to explore a novel aspect of extra-nigral degeneration, the neurodegeneration of spinal cord (SC), in PD. Rotenone administration to male Lewis rats caused significant neuronal cell death in cervical and lumbar SC as compared with control animals. Dying neurons were motoneurons as identified by double immunofluorescent labeling for terminal deoxynucleotidyl transferase, recombinant-mediated dUTP nick-end labeling-positive (TUNEL(+)) cells and choline acetyltransferase (ChAT)-immunoreactivity. Neuronal death was accompanied by abundant astrogliosis and microgliosis as evidenced from glial fibrillary acidic protein (GFAP)-immunoreactivity and OX-42-immunoreactivity, respectively, implicating an inflammatory component during neurodegeneration in SC. However, the integrity of the white matter in SC was not affected by rotenone administration as evidenced from the non co-localization of any TUNEL(+) cells with GFAP-immunoreactivity and myelin basic protein (MBP)-immunoreactivity, the selective markers for astrocytes and oligodendrocytes, respectively. Increased activities of 76 kD active m-calpain and 17/19 kD active caspase-3 further demonstrated involvement of these enzymes in cell death in SC. The finding of ChAT(+) cell death also suggested degeneration of SC motoneurons in rotenone-induced experimental Parkinsonism. Thus, this is the first report of its kind in which the selective vulnerability of a putative parkinsonian target outside of nigrostriatal system has been tested using an environmental toxin to understand the pathophysiology of PD. Moreover, rotenone-induced degeneration of SC motoneuron in this model of experimental Parkinsonism progressed with upregulation of calpain and caspase-3.
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PMID:The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. 1736 52

Parkinson's disease is a neurodegenerative disorder, related to the loss of dopamine (DA)-containing neurons in the substantia nigra. In experimental animals, both vertebrates and invertebrates, rotenone, a commercially available organic pesticide, induces symptoms of Parkinson's disease. We found that that rotenone is toxic to the pond snail Lymnaea stagnalis (4-day LC50 0.8 microM). Rotenone, at concentrations from 0.1 to 5 microM, caused progressive and irreversible behavioural deficits in both acute and chronic exposure. Chronic exposure to 0.5 microM rotenone led to a progressive decrease in spontaneous locomotion and in feeding, reaching almost 100% inhibition of both behaviours by the 7th day of rotenone treatment. In the central nervous system preparation made on the 7th day of treatment the postsynaptic potentials evoked by the identified dopaminergic RPeD1 neuron disappeared whereas the synaptic inputs received by the RPeD1 from a peptidergic neuron (VD4) were still functional. Immunostaining revealed that the tyrosine hydroxylase immunoreactivity decreased below the detectable level in both the RPeD1 cell body and its axonal processes. Finally, HPLC assay showed a significant (25%) decrease in DA level in the CNS by the 7th day of rotenone treatment. We conclude that, as in vertebrates, rotenone disrupts feeding and locomotion of the model mollusc Lymnaea stagnalis. One possible target of rotenone is the dopaminergic neurons in the CNS. We therefore suggest that Lymnaea stagnalis is a suitable invertebrate model for the study of Parkinson's disease, allowing direct analysis of the response of dopaminergic systems to rotenone at behavioural, cellular and neuronal levels.
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PMID:Behavioural and neural deficits induced by rotenone in the pond snail Lymnaea stagnalis. A possible model for Parkinson's disease in an invertebrate. 1743 96

Parkinson's disease is characterized by slow and progressive degeneration of dopaminergic neurons. Increasing evidence has suggested an important role for exposure to pesticides such as rotenone in the pathogenesis of Parkinson's disease. Although rotenone can elicit immune responses in microglia, the intracellular signaling events mediating these effects are poorly defined. Here we show that cell-free supernatants of rotenone-treated monocytic THP-1 cells induced cytotoxicity in dopaminergic neuroblastoma SH-SY5Y cells. Exposure of THP-1 cells to rotenone led to transient production of reactive oxygen species (ROS) and phosphorylation of Akt. Akt activation was also induced by exogenous hydrogen peroxide. Pretreatment of THP-1 cells with either a phosphatidylinositol 3-kinase (PI3K) inhibitor or ROS scavengers prevented Akt activation and protected SH-SY5Y cells from the cytotoxic effect of conditioned media from rotenone-treated THP-1 cells. Rotenone treatment of THP-1 cells also led to upregulation of cyclooxygenase-2 and secretion of prostaglandin E2. These results suggest that rotenone-induced activation of ROS/PI3K/Akt pathway in THP-1 cells leads to the release of factors that are toxic to SH-SY5Y cells and have implications for the onset of Parkinson's disease.
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PMID:Rotenone-induced neurotoxicity of THP-1 cells requires production of reactive oxygen species and activation of phosphatidylinositol 3-kinase. 1748 95

Rotenone is a pesticide that produces a rodent model of Parkinson's disease. Although much evidence suggests that oxidative stress mediates the toxicity of rotenone on dopamine neurons, rotenone can also potentiate glutamate excitotoxicity. We used whole-cell patch pipettes to investigate actions of rotenone on currents evoked by N-methyl-d-aspartate (NMDA) in dopamine neurons in slices of rat midbrain. After superfusing the slice for 20-30 min, rotenone (100 nM) caused a 162% increase in the average amplitude of inward current evoked by 30 microM NMDA. This effect of rotenone was mimicked by the sodium pump inhibitor strophanthidin (10 microM) and was abolished when pipettes contained an ATP regeneration solution. Although strophanthidin also significantly increased the amplitude of inward currents evoked by (+/-)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 10 microM), rotenone failed to potentiate AMPA currents. Because rotenone potentiated NMDA- but not AMPA-dependent currents, this suggests that rotenone acts selectively to augment NMDA receptor function. Furthermore, the failure of rotenone to mimic strophanthidin suggests that rotenone does not inhibit sodium pump activity. Our results suggest that an excitotoxic mechanism might contribute to rotenone neurotoxicity.
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PMID:Rotenone potentiates NMDA currents in substantia nigra dopamine neurons. 1756 Jul 18

Astrocytes maintain homeostasis of neuronal microenvironment, provide metabolic and trophic support to neurons and modulate neuronal responses to injury. Rotenone specifically inhibits mitochondrial complex I, and long exposure to rotenone may increase the risk for Parkinson's disease (PD) and cause Parkinsonism. However, little is known about the role of astrocytes in the process of rotenone-induced dopaminergic neuron injury. In order to investigate this issue, we used MN9D cells as a cell model of dopaminergic neurons and rotenone as a toxin to initiate mitochondrial deficiency. MN9D cells treated with the normal medium or astrocyte-conditioned medium (ACM) were exposed to different concentrations of rotenone for different time followed by cell viability measurement by MTT assay. Besides, various concentrations of ACM and temporally different treatments were devised to evaluate protective efficiency of ACM. Growth curve of cells in the normal medium or ACM was continuously assessed by cell counting for 8 d. The influence of rotenone and ACM on cellular oxidative stress was determined by DCFH-DA staining followed by flow cytometric analysis. Glutathione (GSH) content after treatment of ACM or rotenone was measured by GSH assay kit. Our results showed that rotenone decreased viability of MN9D cells in a dose-dependent manner and ACM treatment significantly attenuated rotenone toxicity at each concentration. No significant difference in growth rate was observed between the normal medium and ACM treatment. Four concentrations of ACM, namely 1/3ACM, 1/2ACM, 2/3ACM and pure ACM, all displayed protection, increasing cell viability to (124.15+/-0.79)%, (126.59+/-0.82) %, (125.84+/-0.61) % and (117.15+/-1.63) % of the cells exposed directly to rotenone, respectively. Treatment with ACM through the whole experiment except the initial 24 h, 24 h before or at the same time of rotenone addition all exerted protective effects, with cell viability being (110.11+/-2.52)%, (113.30+/-2.36) %, (114.42+/-2.00)% of the cells exposed directly to rotenone, respectively. Conversely, ACM treatment 12 h after rotenone addition had no protective effect, with cell viability being (102.54+/-1.36)% of the cells exposed directly to rotenone. Moreover, ACM treatment up-regulated GSH level in MN9D cells nearly twofold. Incubation with 100 nmol/L rotenone for 24 h depleted GSH level by nearly two thirds of the control, but ACM treatment mitigated the drop of GSH level, maintaining its content at (147.83+/-0.63)% of the control. Consistent with GSH change, rotenone administration resulted in a positive rate of 96.24% of DCF staining, implying a great extent of oxidative stress, whereas treatment with ACM reduced the extent of oxidative stress to a positive rate of 78.31%. Taken together, these findings suggest that astrocytes protect MN9D cells from oxidative stress caused by rotenone, and GSH partially accounts for the protection. Therefore, astrocytes may play a protective role in the process of PD.
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PMID:Astrocytes protect MN9D neuronal cells against rotenone-induced oxidative stress by a glutathione-dependent mechanism. 1757 77

Partial inhibition of mitochondrial respiratory complex I by rotenone reproduces aspects of Parkinson's disease in rodents. The hypothesis that rotenone enhancement of neuronal cell death is attributable to oxidative stress was tested in an acute glutamate excitotoxicity model using primary cultures of rat cerebellar granule neurons. As little as 5 nM rotenone increased mitochondrial superoxide (O2*-) levels and potentiated glutamate-induced cytoplasmic Ca2+ deregulation, the first irreversible stage of necrotic cell death. However, the potent cell-permeant O2*- trap manganese tetrakis (N-ethylpyridinium-2yl) porphyrin failed to prevent the effects of the inhibitor. The bioenergetic consequences of rotenone addition were quantified by monitoring cell respiration. Glutamate activation of NMDA receptors used the full respiratory capacity of the in situ mitochondria, and >80% of the glutamate-stimulated respiration was attributable to increased cellular ATP demand. Rotenone at 20 nM inhibited basal and carbonyl cyanide p-trifluoromethoxyphenylhydrazone-stimulated cell respiration and caused respiratory failure in the presence of glutamate. ATP synthase inhibition by oligomycin was also toxic in the presence of glutamate. We conclude that the cell vulnerability in the rotenone model of partial complex I deficiency under these specific conditions is primarily determined by spare respiratory capacity rather than oxidative stress.
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PMID:Spare respiratory capacity rather than oxidative stress regulates glutamate excitotoxicity after partial respiratory inhibition of mitochondrial complex I with rotenone. 1761 Dec 83

Objective To observe the influence of rotenone on the distribution of alpha-synuclein (ASN) in rat model of Parkinson's disease (PD). Methods Wistar rats were randomly divided into two groups and received 2 mg/kg rotenone (s.c.) or sunflower oil (as control group) for about 4 weeks. The hippocampus, substantia nigra and striatum of brain were observed. Hematoxylin and eosin stain were used to observe the Lewy body like inclusion. The expression of tyrosine hydroxylase (TH) or ASN protein was determined by anti-TH or anti-alpha-synuclein immunohistochemistry, respectively. Results In control rats, ASN protein distributed widely in brain, especially in hippocampus, cortex and striatum. Rotenone obviously increased TH positive neurons and fibers loss in substantia nigra and striatum (P < 0.05). In rotenone treated rats, ASN positive cells increased in global brain but not distributed in an even manner. In substantia nigra, ASN positive stuff was found aggregate in both cytoplasm and nucleus, and some formed spherical inclusion; in striatum, ASN positive neurites end aggregated and agglomerated around neurons; and in hippocampus, few dot-like ASN were aggregated in cell body, and no notable change was found in nucleus. Conclusion In rotenone administrated PD rats, ASN protein aggregated in several brain regions but most obviously in striatum and substantia nigra, and the distribution region of ASN was changed from peri-synapse to the cytoplasm and nucleus of dopaminergic neuron.
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PMID:alpha-Synuclein redistributed and aggregated in rotenone-induced Parkinson's disease rats. 1769 Jul 29

Parkinson's disease is a chronic neurodegenerative disorder characterized by loss of dopaminergic neurons in the substantia nigra. Rotenone, a pesticide, produces selective degeneration of dopaminergic neurons and motor dysfunction in rats. To determine the mechanisms underlying rotenone-induced neuronal death, we investigated whether intracellular dopamine plays a role in rotenone (0.1-0.4 microM)-induced apoptosis, using an in vitro model of human dopaminergic SH-SY5Y cells. The 40% decrease of dopamine content by inhibition of dopamine synthesis suppressed rotenone-induced apoptosis. On the other hand, the 30% increase of dopamine content by inhibition of dopamine metabolism enhanced rotenone-induced apoptosis. Depletion of intracellular dopamine using reserpine (0.1-10 microM) also prevented rotenone-induced apoptosis, and this effect was counteracted by dopamine (10-100 microM) replenishment. Inhibition of dopamine reverse transport increased cytosolic dopamine and enhanced rotenone-induced apoptosis. We examined the intracellular localization of dopamine in rotenone-treated cells immunocytochemically and quantitatively. Rotenone induced dopamine redistribution from vesicles to the cytosol. In this process, rotenone stimulated reactive oxygen species and protein carbonylation and decreased an antioxidant, glutathione. Addition of an antioxidant, N-acetylcysteine (3 mM), prevented dopamine being expelled from vesicles and inhibited rotenone-induced apoptosis. Our findings demonstrate that rotenone-generated reactive oxygen species are involved in dopamine redistribution to the cytosol, which in turn may play a role in rotenone-induced apoptosis of dopaminergic cells.
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PMID:Mitochondrial complex I inhibitor rotenone-elicited dopamine redistribution from vesicles to cytosol in human dopaminergic SH-SY5Y cells. 1772 56

Parkinson's disease (PD) is a chronic neurodegenerative disorder characterized by the death of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the subsequent decrease of dopamine levels in the striatum. Epidemiological studies indicate environmental pollutants as a causative factor of sporadic PD. Experimental cell culture models have the inherent problem to mimic long-lasting neurodegeneration and to tackle its time-concentration relationship. The present study was designed to investigate the sensitivity of primary dopaminergic neurons to long-term rotenone exposure relevant to PD. Primary cultures prepared from embryonic mouse mesencephala were treated with nanomolar concentrations of rotenone (1, 3, 5, 10nM) on the 6th day in vitro (DIV) for 2, 4 and 6 days. The number of tyrosine hydroxylase immunoreactive (TH(+)) neurons and total hematoxylin-stained nuclei were counted. Astrocyte density was qualitatively evaluated by anti-glial fibrillary acidic protein (anti-GFAP) immunocytochemistry. It was found that dopaminergic neurons were highly sensitive to long-term rotenone treatment. Rotenone in a concentration- and time-dependent manner decreased the number of TH(+) neurons and led to degenerative changes of their morphology. Counting of the total cell number revealed a significant deleterious effect on the overall culture after 6 days of rotenone exposure. However, our study demonstrates a higher sensitivity of dopaminergic neurons to long-term exposure to nanomolar concentrations of rotenone. Other cells in the culture including non-dopaminergic neurons and glia cells appeared less affected compared to dopaminergic neurons.
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PMID:Dopaminergic neurons are preferentially sensitive to long-term rotenone toxicity in primary cell culture. 1792 80


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