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)

Chronic systemic inhibition of mitochondrial respiratory chain complex I by rotenone causes nigrostriatal dopaminergic degeneration in rats, producing an in vivo experimental model of Parkinson's disease. We recently showed that micromolar Ca2+ concentrations strongly stimulate the release of reactive oxygen species in rotenone-treated isolated rat brain mitochondria. In the present work, we show that the natural antioxidant melatonin inhibits Ca2+ plus rotenone-induced oxidative stress in isolated rat brain mitochondria. In addition, the Ca2+ ionophore A23187 strongly potentiates rotenone-induced death of intact cultured pheochromocytoma (PC12) cells, in a mechanism sensitive to melatonin. Moreover, melatonin inhibits the detection of reactive oxygen species release in PC12 cells treated with rotenone plus A23187. Melatonin does not alter free Ca2+ concentrations or the inhibitory effect of rotenone on mitochondrial complex I. We conclude that micromolar Ca2+ concentrations stimulate neuronal cell death induced by mitochondrial complex I inhibition in a mechanism involving oxidative stress, preventable by the antioxidant melatonin.
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PMID:Protective effect of melatonin on rotenone plus Ca2+-induced mitochondrial oxidative stress and PC12 cell death. 1611 15

Reactive oxygen species (ROS) are important mediators in a number of neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The neuroprotective effects of flavonoids from the stems and leaves of Scutellaria baicalensis Georgi (SSF) against hydrogen peroxide (H2O2)-induced rat pheochromocytoma line PC12 injury were evaluated by cell lesion, free radicals and ATPase disorders. Following a 30 min exposure of the cells to H2O2 (100 microm), a marked decrease in cell survival and activity of superoxide dismutase (SOD) and Na+-K+-ATPase as well as an increase of malondialdehyde (MDA) production and lactate dehydrogenase (LDH) release were observed. Pretreatment of the cells with SSF (18-76 microg/mL) prior to H2O2 exposure notably elevated the cell survival and activity of SOD and Na+-K+-ATPase, and lowered the MDA level and LDH release. Neuroprotection by SSF was also observed in animal models. The present results indicated that SSF exerts neuroprotective effects against H2O2 toxicity, which might be of importance and might contribute to its clinical efficacy for the treatment of neurodegenerative disease.
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PMID:Prevention of oxidative injury by flavonoids from stems and leaves of Scutellaria baicalensis Georgi in PC12 cells. 1639 22

1. Phosphatidylinositol transfer proteins (PI-TP) are responsible for the transport of phosphatidylinositol (PI) and other phospholipids from endoplasmic reticulum to the other membranes and indirectly for lipid mediated signaling. Till now little is known about PI-TPs in brain aging and neurodegeneration. The aim of this study was to investigate expression of PI-TP in the brain during aging and in animal's model of Parkinson disease (PD) induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, in vitro, effect of 1-methyl-4-phenyl-pyridine cation (MPP(+)) on PI-TP, tyrosine hydroxylase (TH) protein level, and viability of cells was investigated. 2. Wistar rats 4, 24, and 36 months old and C57/BL mice and rat pheochromocytoma (PC12) cell line were used for the studies. Mice C57/BL received three injections of MPTP in saline at 2 h intervals in a total dose of 40 mg/kg and then after 3, 7, and 14 days they were used for the investigation. PC12 cells were treated with increasing concentration (50-300 microM) of MPP(+) for 24 h at 37 degrees C. The level of PI-TP(alpha and beta) and TH were determined using Western Blot analysis. 3. Our data indicated that PI-TP(alpha and beta) level decreased in brain of 36 months old rat by 20% comparing to the control value (4 months old). In animal's model of PD, PI-TP(alpha and beta) level was significantly lower by 85, 69, 64% in striatum at 3, 7, and 14 days after MPTP injection, respectively, compared to the control value. MPP(+) decreased PI-TP(alpha and beta), TH expression, and viability of PC12 cells in a dose-dependent manner. H(2)O(2), menadione, and NO donor significantly decreased the PI-TP level and viability of PC12 cells. 4. Our results indicate the lower protein expression of PI-TP(alpha and beta) in aged brain and in PD and suggest that oxidative stress may be responsible for the alteration of PI-TP.
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PMID:Phosphatidylinositol transfer protein expression altered by aging and Parkinson disease. 1677 71

Chloral-derived beta-carbolines, which are structurally similar to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 5), are discussed to contribute to neuronal cell death in idiopathic Parkinson's disease. The cytotoxicity of 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo, 4) to neuronal-like clonal pheochromocytoma PC12 cells was examined by the determination of lactate dehydrogenase (LDH) release. After incubation for 48 h, 4 showed a strong dose-dependent cytotoxic activity towards PC12 cells with an ED50 value of 230 microM. In PC12 cells reductive dehalogenation of 4 was observed giving rise to the formation of 1-dichloromethyl-1,2,3,4-tetrahydro-beta-carboline (6) as a main TaClo metabolite exhibiting a cytotoxic potential comparable to that of TaClo. An X-ray structure analysis, performed for the trifluoroacetyl derivative of 6, revealed the N-substituent of such a highly chlorinated agent to be dramatically pushed out of the beta-carboline ring 'plane' due to the high steric demand of the huge dichloromethyl group at C(1).
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PMID:Toxicity and metabolism of the chloral-derived mammalian alkaloid 1-trichloromethyl-1,2,3,4-tetrahydro-beta-carboline (TaClo) in PC12 cells. 1698 24

Nerve growth factor (NGF) differentiated pheochromocytoma PC12 cells exposed to 1-methyl-4-phenylpyridinium (MPP+) toxin were used as an in vitro pharmacological model of Parkinson's disease to examine the neuroprotective effects of 4-hydroxy-2,2,6,6-tetramethyl piperidine-n-oxyl (Tempol), a free radical scavenger and a superoxide dismutase-mimetic compound. MPP+-induced PC12 cell death was measured 72 h after exposure to 1.5 mM MPP+ by the release of lactate dehydrogenease, caspase-3 activation and stimulation of survival and stress mitogen-activated protein kinases. Exposure of PC12 cells to MPP+ activated ERK1 and ERK2 (forty-fold over control after 72 h), JNK1 and JNK2 (fourfold after 48 h) and p-38alpha (tenfold after 24 h). Pretreatment of PC12 cells with 500 microM Tempol, 1 h before induction of the MPP+ insult, reduced by 70% the release of LDH into the medium, inhibited caspase-3 activity by 30% and improved by 33% mitochondrial function, effects correlated with a 70% reduction in ERK1 and ERK2 phosphorylation activity. These findings support the neuroprotective effect of Tempol in the MPP+-induced PC12 cell death model and its use as a potential drug for treatment of Parkinson's disease.
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PMID:Neuroprotective effects of the stable nitroxide compound Tempol on 1-methyl-4-phenylpyridinium ion-induced neurotoxicity in the Nerve Growth Factor-differentiated model of pheochromocytoma PC12 cells. 1698 7

HFS has become a widely used method in functional neurosurgery. However, its mechanism is not well understood, and its cellular and molecular effects have not yet been investigated. The aim of the study was to understand which cellular events, unrelated to the network organization of cells or neurons, participate in the mechanism of action of HFS. In vitro cellular effects of high (HFS) and low (LFS) frequency electrical stimulation on prolactin secretion in GH3 cell lines (prolactinoma), as well as the catecholaminergic secretion on PC12 cells (pheochromocytoma) were investigated. Cells were cultured in dishes with integrated electrodes to deliver stimulation at the same parameters as those used in clinical conditions to treat advanced forms of Parkinson's disease. Prolactin production was measured in GH3 using a Radio-Immuno-Assay. Dopamine, epinephrine and norepinephrine were measured in PC12 using Enzymo-immuno-assays. HFS for 24 hours reduced prolactin secretion by 40.3%, dopamine by 32.7%, epinephrine by 18.1% (non significant) and norepinephrine by 27.0%. LFS did not induce significant changes. These results suggest that HFS has an inhibitory impact on the cellular machinery responsible for hormone and neurotransmitter production. In this model of isolated cultured cells, network interactions and particularly presynaptic actions are discarded. HFS has inhibitory effects on cellular mechanisms responsible for the production and release of molecules participating in intercellular communication. This HFS-induced inhibition might participate in the lesion-like effect of therapeutic HFS in the basal ganglia during various movement disorders.
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PMID:Alteration of hormone and neurotransmitter production in cultured cells by high and low frequency electrical stimulation. 1717 Dec 96

A number of studies indicate that reactive oxygen species (ROS) are involved in neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD). The neuroprotective effects of salvianolic acid B (SalB) from Radix Salviae miltiorrhizae (RSM) against hydrogen peroxide (H2O2)-induced rat pheochromocytoma line PC12 injury were evaluated in the present study. Vitamin E, a potent antioxidant, was employed as a positive control agent. Following exposure of cells to H2O2 (150 microM), a marked decrease in cell survival and activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px), as well as increased levels of malondialdehyde (MDA) production and lactate dehydrogenase (LDH) release were observed. In parallel, H2O2 caused significant elevation in intracellular Ca2+ level and caspase-3 activity, and induced apoptotic death as determined by flow cytometric assay. However, pretreatment of the cells with SalB (0.1-10 microM) prior to H2O2 exposure blocked these H2O2-induced cellular events noticeably. Moreover, SalB exhibited significantly higher potency as compared to Vitamin E. The present findings indicated that SalB exerts neuroprotective effects against H2O2 toxicity, which might be of importance and contribute to its clinical efficacy for the treatment of neurodegenerative diseases.
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PMID:Protection of PC12 cells from hydrogen peroxide-induced cytotoxicity by salvianolic acid B, a new compound isolated from Radix Salviae miltiorrhizae. 1717 50

The potential cytoprotective effects of the anti-leprosy antibiotic rifampicin were investigated in rat pheochromocytoma (PC12) cells prior to intoxication with 1-Methyl-4-phenyl pyridinium (MPP(+)). MPP(+) induced both apoptotic and necrotic cell death, and increased the expression of a 57 kDa species of alpha-Synuclein. This species of alpha-Synuclein is larger than the monomer, and is therefore an oligomer or an aggregated form of the protein. Rifampicin significantly increased survival of these catecholaminergic cells in a concentration-dependent manner. The expression of the higher molecular mass alpha-Synuclein was increased by MPP(+) exposure, and its expression was inversely related to cell survival in the rifampicin-treated cells. Importantly, rifampicin suppressed apoptosis almost completely, without shifting the death cascade to necrosis, which is a problem that has been reported with caspase inhibitors of apoptosis (Hartmann, A., Troadec, J.D., Hunot, S., Kikly, K., Faucheux, B.A., Mouatt-Prigent, A., Ruberg, M. Agid, Y., Hirsch, E.C., 2001. Caspase-8 is an effector in apoptotic death of dopaminergic neurons in Parkinson's disease, but pathway inhibition results in neuronal necrosis. J. Neurosci. 21, 2247-2255). These results suggest that rifampicin improves survival of catecholamine- and alpha-Synuclein-containing cells, which degenerate in Parkinson's disease (PD), and thus may be therapeutic in this disease.
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PMID:Rifampicin protects PC12 cells against MPP+-induced apoptosis and inhibits the expression of an alpha-Synuclein multimer. 1728 Jun 46

Parkinson's disease (PD) is characterized by selective loss of dopaminergic neurons in the substantia nigra of the brain. Although the underlying causes are not well characterized, epidemiological studies suggest an elevated risk of PD with occupational pesticide exposure. Here, we utilized pheochromocytoma (PC) 12 and SH-SY5Y cells as well as rat primary cultured dopaminergic neurons to investigate mechanisms for dopaminergic cell death induced by paraquat and rotenone, pesticides that are used to model PD in rodents. Both paraquat and rotenone induce selective loss of dopaminergic neurons in primary cultures. We discovered that paraquat induces apoptosis in PC12 cells but not in SH-SY5Y cells, while rotenone exposure causes apoptosis in SH-SY5Y cells but not in PC12 cells. The selective ability of paraquat and rotenone to induce apoptosis in different cell lines correlates with their ability to activate c-Jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinases. Furthermore, JNK and p38 are required for rotenone-induced apoptosis in SH-SY5Y cells (K. Newhouse et al., 2004, Toxicol. Sci. 79, 137-146) as well as primary neurons, and for paraquat-induced apoptosis in PC12 cells. However, JNK but not p38 plays a role in paraquat-induced loss of primary cultured dopaminergic neurons. Our data identify JNK activation as a common mechanism underlying dopaminergic cell death induced by both paraquat and rotenone in model cell lines and primary cultures.
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PMID:Activation of c-Jun N-terminal protein kinase is a common mechanism underlying paraquat- and rotenone-induced dopaminergic cell apoptosis. 1732 51

D-beta-hydroxybutyrate (DbetaHB) is a predominant member of ketone bodies produced by hepatocytes and, to a lesser extent, by astrocytes. It is an alternative source of energy in the brain when glucose supply is depleted such as during starvation. It has been reported that ketone bodies could protect dopaminergic culture. However, the biological function of DbetaHB in Parkinson disease (PD) is still unclear. In the present work, we investigated the role of DbetaHB in protecting rat pheochromocytoma (PC12) cells from apoptosis induced by 6-Hydroxydopamine (6-OHDA). DbetaHB rescued PC12 cells from apoptotic death induced by 6-OHDA by MTT assay, acridine orange (AO) staining, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining and the activity of caspase-3. DbetaHB prevented the decrease of cell viability and the increase of caspase-3 activity induced by 6-OHDA in a dose-dependent manner in PC12 cells. AO and TUNEL staining showed that DbetaHB prevented the apoptosis of PC12 cells induced by 6-OHDA. The ratio of Bcl-2/Bax at mRNA levels, which regulates the apoptosis of PC12 cells when exposed to 6-OHDA, increased when DbetaHB was preincubated. The data showed that DbetaHB inhibited the apoptosis of PC12 cells induced by 6-OHDA in relation to up-regulating the ratio of Bcl-2/Bax mRNA.
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PMID:D-beta-hydroxybutyrate inhibits the apoptosis of PC12 cells induced by 6-OHDA in relation to up-regulating the ratio of Bcl-2/Bax mRNA. 1736 4


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