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)

Ropinirole, a D2/D3 receptor agonist has been reported to have neuroprotective effects. We showed that ropinirole can prevent rotenone-induced apoptosis in dopaminergic cell line SH-SY5Y through D3 receptor. We found that ropinirole can block the rotenone-induced phosphorylation of JNK, P38 and p-c-Jun, but promote the phosphorylation of ERK1/2. Furthermore, we demonstrated that ropinirole can reduce the rotenone-induced cleavages of caspase 9, caspase 3 and PARP and elevate the expression of anti-apoptotic proteins of p-Akt and bcl-2. These results provide a basis for neuroprotection by this drug for the treatment of Parkinson disease.
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PMID:D2/D3 receptor agonist ropinirole protects dopaminergic cell line against rotenone-induced apoptosis through inhibition of caspase- and JNK-dependent pathways. 1824 71

The neurotoxicity of l-3,4-dihydroxyphenylalanine (L-DOPA), used for the treatment of Parkinson's disease, remains controversial. Although there are many reports suggesting that long-term treatment of L-DOPA causes neuronal death, an increasing body of recent evidence has proposed that L-DOPA might be neuroprotective rather than neurotoxic. We investigated the effect of L-DOPA on neuronally differentiated PC12 (nPC12) cells by treating cells with various concentrations of L-DOPA for 24h. We also studied whether glycogen synthase kinase (GSK)-3 activation is related to L-DOPA-induced neurotoxicity by simultaneously treating cells with several concentrations of L-DOPA and a GSK-3 inhibitor for 24h. MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, trypan blue staining, cell counting kit-8, and DAPI staining all showed that L-DOPA decreased nPC12 cell viability at high concentrations. In addition, 100 microM L-DOPA treatment significantly increased the activity of GSK-3 and death signals including cytochrome c, activated caspase-3 and cleaved PARP, and decreased survival signals including heat shock transcription factor-1 in a concentration-dependent manner. Treatment with GSK-3 inhibitor VIII or lithium chloride prevented L-DOPA-induced cell death. Together, these results suggest that L-DOPA induces neuronal cell death at high concentrations and that the neurotoxic effect of L-DOPA might be mediated in part by GSK-3 activation.
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PMID:Inhibition of glycogen synthase kinase-3 reduces L-DOPA-induced neurotoxicity. 1838 27

Parkinson's disease (PD) has been proposed to result from a combination of genetic susceptibility and environmental exposure. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in neuron degeneration and in pathogenesis of PD. Nurr1, a member of nuclear receptor superfamily, is a potential susceptibility gene for PD. In this in vitro and in vivo study, we investigated whether Nurr1 deficiency may predispose to environmental proteasome inhibitors-induced neuron injury. We found that lactacystin, an irreversible proteasome inhibitor, caused greater injury to SH-SY5Y cells that Nurr1 expression has been suppressed by small interference RNA (siRNA). On the contrary, the Nurr1 overexpressed SH-SY5Y cells by Nurr1 expression vector transfection rescued the lactacystin-induced injury. In vivo, stereotactic microinjection with lactacystin into right median forebrain bundle (MFB) of mice caused significant inhibition of the proteasome activity in both Nurr1 knock out heterozygous (Nurr1 +/-) mice and their littermate wild-type (Nurr1 +/+) mice. At same time, we found that there was a severer loss of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) and greater reduction of striatal dopamine (DA) levels in Nurr1 +/- mice as compared with that in Nurr1 +/+ mice. Furthermore, lactacystin-induced increase of cleaved PARP, cleaved caspase3 and p53 and decrease of bcl-2 in SN was significantly enhanced in Nurr1 +/- mice. These findings suggest that reduction in Nurr1 expression increases susceptibility to DAergic neuron injury induced by UPS impairment.
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PMID:Nurr1 deficiency predisposes to lactacystin-induced dopaminergic neuron injury in vitro and in vivo. 1857 22

Dopamine-induced neuronal cytotoxicity has been proposed as a leading pathological mechanism underlying many neuronal degenerative disorders including Parkinson disease. Various hypotheses have been proposed including oxidative stress and dopamine (DA)-induced intracellular signal disorder via DA D1 and D2 receptors. The exact mechanism involved in this process is far from clear. In this study, employing a neuronal blastoma cell line, SH-SY5Y, we tried to elucidate the roles of these different suggested mechanisms in this pathological process. The results showed that DA induced cell toxicity in a dose- and time-dependent way. Selective D1 and D2 DA receptor antagonist could not block the cytotoxic effects, whereas reductive reagent ascorbic acid but not GSH could effectively rescue the cell death, suggesting that DA-induced cell toxicity was caused by an extracellular oxidative stress. This was further supported by the enhancing effects of DA transporter blocker, GBR, which could increase the cell death when pretreated. Finally, ascorbic acid could also protect SY5Y cells from DA-induced cellular apoptotic signal changes including PARP and P53. Our studies suggested that DA exerted its cytotoxic effects via an extracellular metabolism, whereas intracellular transportation could reduce its oxidative stress. Cytotoxicity effects induced by extracellular DA could be protected by reductive agents as ascorbic acid. These results help to broaden our understanding of the mechanisms of DA-induced cell death and may provide potentially therapeutical alternative for the neurodegenerative disorders.
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PMID:Extracellular dopamine induces the oxidative toxicity of SH-SY5Y cells. 1872 Apr 20

Reduced folates have been shown to reconstitute the proper activity of "uncoupled" endothelial nitric oxide synthase in inflamed endothlelium. There is recent evidence that this phenomenon may reflect an ability of reduced folates to scavenge peroxynitrite - or, more likely, nitrogen dioxide and carbonate radicals derived from carbonate-induced decomposition of peroxynitrite. This suggests that, at least in those tissues capable of achieving high intracellular levels of reduced folates following high-dose folate administration, high-dose folate may have important anti-inflammatory potential. It would be of interest to examine the impact of high-dose folate in rodent models of disorders in which peroxynitrite plays a key pathogenic role - including diabetes, septic or hemorrhagic shock, ischemia-reperfusion, congestive heart failure, and inflammatory mutagenesis. In particular, this strategy may be useful in many pathologies in which oxidant-mediated PARP activation leads to cell death or dysfunction. Recent evidence that high-dose folate administration preserves myocyte viability following cardiac ischemia-reperfusion likely reflects folate's impact on the cytotoxicity of peroxynitrite. For use in medical emergencies, parenteral leucovorin (racemic 5-formyltetrahydrofolate) is already clinically available. Since uric acid can also function physiologically as a scavenger of peroxynitrite-derived radicals, supplemental inosine or dietary nucleic acids - which raise tissue levels of urate more effectively than does oral uric acid - may usefully complement the protective impact of high-dose folate on nitroxidative stress. Epidemiological associations of high urate levels with low risk for Parkinson's disease may reflect urate's radical scavenging activity, and suggest the possible utility of dietary purines in prevention or treatment of CNS inflammatory disorders.
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PMID:High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals--clinical potential in inflammatory disorders. 1940 16

Elevated oxidative stress-induced apoptosis has been found in peripheral cells from patients with Alzheimer's disease (AD). Furthermore, treatment of lymphocytes from AD patients, with Abeta(1-42) and H(2)O(2) results in enhanced apoptosis. Mild cognitive impairment (MCI), a clinical condition between normal aging and AD, shares with AD a similar pattern of peripheral markers of oxidative stress. In this study we investigated spontaneous and H(2)O(2)-induced oxidative stress and apoptosis levels in peripheral blood mononuclear cells (PBMCs) from MCI and AD patients, as well as from Parkinson's disease (PD) patients without cognitive impairment or age-matched healthy control. Sod1 mRNA levels were studied to analyse the anti-oxidative pathway, while Bax and Bcl-2 mRNAs levels and PARP protein cleavage were monitored to study apoptosis. We found that the expression of Sod1 and Bax mRNAs was statistically higher in both MCI and AD patients compared to controls or PD subjects. Since Bcl-2 mRNA level was not different among groups, the Bax/Bcl-2 ratio was statistically higher in AD and MCI patients. PARP cleavage was also enhanced in PBMCs from MCI and AD individuals and this finding was associated with a higher level of spontaneous apoptosis. Interestingly, exposure to H(2)O(2) induced a significant decrease of Bcl-2 mRNA transcript, while Sod1 and Bax mRNAs levels were unchanged in PBMCs derived from MCI and AD patients. In conclusion, our results show that Bax and Sod1 mRNA levels are altered in PBMCs from both MCI and AD patients and indicate these changes as potential biomarkers in the early diagnosis of AD.
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PMID:Peripheral blood mononuclear cells from mild cognitive impairment patients show deregulation of Bax and Sod1 mRNAs. 1942 11

Rotenone is a pesticide that has been shown to induce the pathological symptoms of Parkinson's disease (PD) in animal models. In this study, we investigated the protective effects of tranexamic acid (TA) on rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells. TA blocked the rotenone-induced phosphorylation of JNK and P38, the downregulation of BCL2 and the upregulation of BAX. Furthermore, TA not only decreased the rotenone-induced cleavage of caspase 9, PARP, and caspase 3, but also increased caspase 3 enzymatic activity. Our findings indicate that TA is able to protect neuronal cells against apoptosis and suggest that TA might potentially serve as an agent for prevention or therapy of PD.
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PMID:Tranexamic acid protects against rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. 1953 6

Parkinson's disease (PD) is caused by degeneration of the dopaminergic (DA) neurons of the substantia nigra but the molecular mechanisms underlying the degenerative process remain elusive. Several reports suggest that cell cycle deregulation in post-mitotic neurons could lead to neuronal cell death. We now show that Parkin, an E3 ubiquitin ligase linked to familial PD, regulates beta-catenin protein levels in vivo. Stabilization of beta-catenin in differentiated primary ventral midbrain neurons results in increased levels of cyclin E and proliferation, followed by increased levels of cleaved PARP and loss of DA neurons. Wnt3a signaling also causes death of post-mitotic DA neurons in parkin null animals, suggesting that both increased stabilization and decreased degradation of beta-catenin results in DA cell death. These findings demonstrate a novel regulation of Wnt signaling by Parkin and suggest that Parkin protects DA neurons against excessive Wnt signaling and beta-catenin-induced cell death.
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PMID:Parkin protects dopaminergic neurons from excessive Wnt/beta-catenin signaling. 1959 2

Histamine H(2) receptor antagonists have been reported to improve the motor symptoms of Parkinson's disease (PD) patients and to exert neuroprotective effects. In this study, we investigated the protective effects of the H(2) receptor antagonist ranitidine on rotenone-induced apoptosis in human dopaminergic SH-SY5Y cells, focusing on mitogen-activated protein kinases (MAPKs) and caspases (CASPs)-mediated apoptotic events. Ranitidine blocked the rotenone-induced phosphorylation of c-Jun NH(2)-terminal protein kinase (JNK) and P38 MAPK (P38), and promoted the phosphorylation of extracellular signal-regulated protein kinase (ERK). Ranitidine also prevented the down-regulation of B-cell CLL/lymphoma 2 (BCL2) and the up-regulation of BCL2-associated X protein (BAX) by rotenone. Furthermore, ranitidine not only attenuated rotenone-induced cleavages of CASP9, poly(ADP-ribose) polymerase-1 (PARP) and CASP3, but also suppressed CASP3 enzyme activity. These results indicate that ranitidine protects against rotenone-induced apoptosis, inhibiting phosphorylation of JNK and P38, and activation of CASPs in human dopaminergic SH-SY5Y cells.
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PMID:Protective effect of histamine H2 receptor antagonist ranitidine against rotenone-induced apoptosis. 1972 37

VPS41 is a protein identified as a potential therapeutic target for Parkinson's disease (PD) as a result of a high-throughput RNAi screen in Caenorhabditis elegans. VPS41 has a plausible mechanistic link to the pathogenesis of PD, as in yeast it is known to participate in trafficking of proteins to the lysosomal system and several recent lines of evidence have pointed to the importance of lysosomal system dysfunction in the neurotoxicity of alpha-synuclein (alpha-syn). We found that expression of the human form of VPS41 (hVPS41) prevents dopamine (DA) neuron loss induced by alpha-syn overexpression and 6-hydroxydopamine (6-OHDA) neurotoxicity in C. elegans. In SH-SY5Y neuroblastoma cell lines stably transfected with hVPS41, we determined that presence of this protein conferred protection against the neurotoxins 6-OHDA and rotenone. Overexpression of hVPS41 did not alter the mitochondrial membrane depolarization induced by these neurotoxins. hVPS41 did, however, block downstream events in the apoptotic cascade including activation of caspase-9 and caspase-3, and PARP cleavage. We also observed that hVPS41 reduced the accumulation of insoluble high-molecular weight forms of alpha-syn in SH-SY5Y cells after treatment with rotenone. These data show that hVPS41 is protective against both alpha-syn and neurotoxic-mediated injury in invertebrate and cellular models of PD. These protective functions may be related to enhanced clearance of misfolded or aggregated protein, including alpha-syn. Our studies indicate that hVPS41 may be a useful target for developing therapeutic strategies for human PD.
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PMID:VPS41, a protein involved in lysosomal trafficking, is protective in Caenorhabditis elegans and mammalian cellular models of Parkinson's disease. 1985 Jan 27


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