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)

Dopamine (DA) modulates apoptosis in neuronal and non-neuronal cells, and dopaminergic pathways contribute to neurodegenerative disease. Human lymphocytes express dopaminergic receptors and DA transporters, and synthesize endogenous catecholamines, which may modulate apoptosis in these cells. In the present study, dopaminergic modulation of apoptosis was investigated in human peripheral blood mononuclear cells (PBMCs) obtained from healthy donors. Twenty-four-hour DA reduced at 0.1-5 x 3 10(-6) M and enhanced at 1-5 x 310(-4) M spontaneous apoptosis. DA 1 x 310(-6) M was inhibited by the D1-like receptor antagonist SCH 23390 1 x 310(-6) M, but not by the D2-like receptor antagonists domperidone 1 x 3 10(-6) M or haloperidol 1 x 3 10(-6) M, while the effect of DA 5 x 3 10(-4) M was prevented by the antioxidants glutathione 5-10 mM or N-acetyl-l-cysteine 1-10 mM. Intracellular reactive oxygen species were respectively reduced and increased by 1-3 h incubation with DA 0.1-10 x 3 10(-6) M and 1-5x310(-4) M. Twenty-four-hour DA 1 x 3 10(-6) M or 5 x 3 10(-4) M had no effect on PBMC expression of Cu/Zn superoxide dismutase or Bcl-2; however, DA 5 x 3 10(-4) M decreased caspase-3 activity. In human PBMCs, DA seems to promote apoptosis through oxidative mechanisms but may also result in cell rescue from apoptotic death possibly through activation of D1-like receptors. The dual effect of DA on human PBMCs closely resembles that on striatal neurons. Lymphocytes of patients with Parkinson's disease may show reduced DA content and impaired DA transporter immunoreactivity. Human PBMCs may thus represent a simple and readily accessible model to study DA-related mechanisms relevant for neurodegenerative disease.
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PMID:Dopaminergic modulation of apoptosis in human peripheral blood mononuclear cells: possible relevance for Parkinson's disease. 1503 11

We previously demonstrated that the organochlorine pesticide dieldrin, a potential chemical risk factor for development of Parkinson's disease (PD), impairs mitochondrial function and promotes apoptosis in dopaminergic PC12 cells. We further demonstrated that caspase-3-dependent proteolytic activation of a member of the novel PKC family, protein kinase Cdelta (PKCdelta), contributes to apoptotic cell death in dopaminergic cells. In the present study, we report that the proapoptotic function of PKCdelta can be regulated by overexpression of the mitochondrial anti-apoptotic protein Bcl2 in dieldrin-treated dopaminergic cells. Exposure to dieldrin (30 or 100 micro M) for 3 h produced a dose-dependent increase in caspase-3 activation and DNA fragmentation in vector-transfected PC12 cells. Overexpression of human Bcl-2 in PC12 cells completely suppressed dieldrin-induced caspase-3 activation and DNA fragmentation. Furthermore, dieldrin-induced proteolytic activation of PKCdelta was also remarkably reduced in Bcl-2-overexpressed cells. Together, these results suggest that the proapoptotic function of PKCdelta can be regulated by mitochondrial redox modulators during neurodegenerative processes.
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PMID:Proteolytic activation of proapoptotic kinase PKCdelta is regulated by overexpression of Bcl-2: implications for oxidative stress and environmental factors in Parkinson's disease. 1503 12

The endogenous neurotoxin, 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline (salsolinol), has been considered a potential neurotoxin in the etiology of Parkinson's disease (PD). Salsolinol and N-methyl(R)-salsolinol were identified in the brains and cerebrospinal fluid (CSF) of PD patients. Oxidative stress is known to be one of the major contributing factors in the cascade that may finally leads to the cell death in PD. The present study was undertaken to understand the role of salsolinol in oxidative-mediated neuronal toxicity in dopaminergic SH-SY5Y cells, and the neuroprotective effects of metallothionein (MT) against salsolinol toxicity in MT overexpressing (MT(trans)) fetal mesencephalic cells. Salsolinol increased the production of reactive oxygen species (ROS) and significantly decreased glutathione (GSH) levels and cell viability in SH-SY5Y cells. Salsolinol also decreased intracellular ATP levels and induced nuclear condensation in these cells. Salsolinol-induced depletion in cell viability was completely prevented by N-acetylcysteine in SH-SY5Y cells, and also prevented by MT in MT(trans) fetal mesencephalic cells compared to control(wt) cells. The extent of nuclear condensation and caspase activation was also less in MT(trans) cells than control(wt) cells. These results suggest that salsolinol causes oxidative stress by decreasing the levels of GSH and by increasing ROS production, and these events may lead to the death of dopaminergic cell. Furthermore, MT overexpression may protect dopaminergic neurons against salsolinol-induced neurotoxicity, most probably by the inhibition of oxidative stress and apoptotic pathways including caspase-3 activation.
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PMID:Salsolinol, a dopamine-derived tetrahydroisoquinoline, induces cell death by causing oxidative stress in dopaminergic SH-SY5Y cells, and the said effect is attenuated by metallothionein. 1504 66

Astrocytes, the most abundant glial cell types in the brain, provide metabolic and trophic support to neurons and modulate synaptic activity. Accordingly, impairment in these astrocyte functions can critically influence neuronal survival. Recent studies show that astrocyte apoptosis may contribute to pathogenesis of many acute and chronic neurodegenerative disorders, such as cerebral ischemia, Alzheimer's disease and Parkinson's disease. We found that incubation of cultured rat astrocytes in a Ca(2+)-containing medium after exposure to a Ca(2+)-free medium causes an increase in intracellular Ca(2+) concentration followed by apoptosis, and that NF-kappa B, reactive oxygen species, and enzymes such as calpain, xanthine oxidase, calcineurin and caspase-3 are involved in reperfusion-induced apoptosis. Furthermore, we demonstrated that heat shock protein, mitogen-activated protein/extracellular signal-regulated kinase, phosphatidylinositol-3 kinase and cyclic GMP phosphodiesterase are target molecules for anti-apoptotic drugs. This review summarizes (1) astrocytic functions in neuroprotection, (2) current evidence of astrocyte apoptosis in both in vitro and in vivo studies including its molecular pathways such as Ca(2+) overload, oxidative stress, NF-kappa B activation, mitochondrial dysfunction, endoplasmic reticulum stress, and protease activation, and (3) several drugs preventing astrocyte apoptosis. As a whole, this article provides new insights into the potential role of astrocytes as targets for neuroprotection. In addition, the advance in the knowledge of molecular mechanisms of astrocyte apoptosis may lead to the development of novel therapeutic strategies for neurodegenerative disorders.
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PMID:Astrocyte apoptosis: implications for neuroprotection. 1506 28

The causes of sporadic Parkinson's disease (PD) are poorly understood. 6-Hydroxydopamine (6-OHDA), a PD mimetic, is widely used to model this neurodegenerative disorder in vitro and in vivo; however, the underlying mechanisms remain incompletely elucidated. We demonstrate here that 6-OHDA evoked endoplasmic reticulum (ER) stress, which was characterized by an up-regulation in the expression of GRP78 and GADD153 (Chop), cleavage of procaspase-12, and phosphorylation of eukaryotic initiation factor-2 alpha in a human dopaminergic neuronal cell line (SH-SY5Y) and cultured rat cerebellar granule neurons (CGNs). Glycogen synthase kinase-3 beta (GSK3beta) responds to ER stress, and its activity is regulated by phosphorylation. 6-OHDA significantly inhibited phosphorylation of GSK3beta at Ser9, whereas it induced hyperphosphorylation of Tyr216 with little effect on GSK3beta expression in SH-SY5Y cells and PC12 cells (a rat dopamine cell line), as well as CGNs. Furthermore, 6-OHDA decreased the expression of cyclin D1, a substrate of GSK3beta, and dephosphorylated Akt, the upstream signaling component of GSK3beta. Protein phosphatase 2A (PP2A), an ER stress-responsive phosphatase, was involved in 6-OHDA-induced GSK3beta dephosphorylation (Ser9). Blocking GSK3beta activity by selective inhibitors (lithium, TDZD-8, and L803-mts) prevented 6-OHDA-induced cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), DNA fragmentations and cell death. With a tetracycline (Tet)-controlled TrkB inducible system, we demonstrated that activation of TrkB in SH-SY5Y cells alleviated 6-OHDA-induced GSK3beta dephosphorylation (Ser9) and ameliorated 6-OHDA neurotoxicity. TrkB activation also protected CGNs against 6-OHDA-induced damage. Although antioxidants also offered neuroprotection, they had little effect on 6-OHDA-induced GSK3beta activation. These results suggest that GSK3beta is a critical intermediate in pro-apoptotic signaling cascades that are associated with neurodegenerative diseases, thus providing a potential target site amenable to pharmacological intervention.
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PMID:Glycogen synthase kinase 3beta (GSK3beta) mediates 6-hydroxydopamine-induced neuronal death. 1513 87

Environmental exposure to the oxidant-producing herbicide paraquat has been implicated as a risk factor in Parkinson's disease. Although intraperitoneal paraquat injections in mice cause a selective loss of dopaminergic neurons in the substantia nigra pars compacta, the exact mechanism involved is still poorly understood. Our data show that paraquat induces the sequential phosphorylation of c-Jun N-terminal kinase (JNK) and c-Jun and the activation of caspase-3 and sequential neuronal death both in vitro and in vivo. These effects are diminished by the specific JNK inhibitor SP600125 and the antioxidant manganese(III) tetrakis (4-benzoic acid) porphyrin in vitro. Furthermore, JNK pathway inhibitor CEP-11004 effectively blocks paraquat-induced dopaminergic neuronal death in vivo. These results suggest that the JNK signaling cascade is a direct activator of the paraquat-mediated nigral dopaminergic neuronal apoptotic machinery and provides a molecular linkage between oxidative stress and neuronal apoptosis.
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PMID:The herbicide paraquat induces dopaminergic nigral apoptosis through sustained activation of the JNK pathway. 1515 44

We examined the toxicity of paraquat, a possible environmental risk factor for neurodegenerative disorders like Parkinson's disease (PD). Paraquat is structurally similar to the neurotoxin MPP+ that can induce Parkinsonian-like features in rodents, non-human primates and human. Exposure of cerebellar granule cells to relatively low concentrations of paraquat (5 microM) produces apoptotic cell death with a reduction in mitochondrial cytochrome c content, proteolytic activation and caspase-3 activity increase and DNA fragmentation. Paraquat-induced apoptosis was significantly attenuated by co-treatment of cerebellar granule cells with the radical scavenger vitamin E, suggesting that paraquat-induced free radicals serve as important signal in initiation of cell death. As a decrease in mitochondrial cytochrome c content is also prevented by allopurinol, we suggest that xanthine oxidase plays an important role in the free radical production that precedes the apoptotic cascade and cell death after paraquat exposition.
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PMID:Paraquat-induced apoptotic cell death in cerebellar granule cells. 1515 3

Manganese (Mn) is an essential metal that, at excessive levels in the brain, produces extrapyramidal symptoms similar to those in patients with Parkinson's disease (PD). In the present study, Mn toxicity was characterized in a human neuroblastoma (SK-N-SH) cell line and in a mouse catecholaminergic (CATH.a) cell line. Mn was demonstrated to be more toxic in the catecholamine-producing CATH.a cells (EC50 = 60 microM) than in non-catecholaminergic SK-N-SH cells (EC50 = 200 microM). To test the hypothesis that the sensitivity of CATH.a cells to Mn is associated with their dopamine (DA) content, DA concentrations were suppressed in these cells by pretreatment with alpha-methyl-para-tyrosine (AMPT). Treatment for 24 h with 100 microM AMPT decreased intracellular DA, but offered no significant protection from Mn exposure (EC50 = 60 microM). Additional studies were carried out to assess if Mn toxicity was dependent on glutathione (GSH) levels. CATH.a cells were significantly protected by the addition of 5mM GSH (Mn EC50 = 200 microM) and 10mM N-acetyl cysteine (NAC) (Mn EC50 = 300 microM), therefore, indirectly identifying intracellular ROS formation as a mechanism for Mn neurotoxicity. Finally, apoptotic markers of Mn-induced cell death were investigated. DNA fragmentation, caspase-3 activation, and apoptosis-related gene expression were studied in CATH.a cells. No internucleosomal fragmentation or caspase activation was evident, even in the presence of "supraphysiological" Mn concentrations. cDNA hydridization array analysis with two differing Mn concentrations and time points, identified no noteworthy mRNA inductions of genes associated with programmed cell death. In conclusion, DA content was not responsible for the enhanced sensitivity of CATH.a cells to Mn toxicity, but oxidative stress was implicated as a probable mechanism of cytotoxicity.
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PMID:Manganese-induced cytotoxicity in dopamine-producing cells. 1518 9

One experimental therapy for Parkinson's disease (PD) is the transplantation of embryonic ventral mesencephalic tissue. Unfortunately, up to 95% of grafted neurons die, many via apoptosis. Activated caspases play a key role in execution of the apoptotic pathway; therefore, exposure to caspase inhibitors may provide an effective intervention strategy for protection against apoptotic cell death. In the present study we examined the efficacy of two different caspase inhibitors, caspase-1 inhibitor Ac-YVAD-CMK and caspase-3 inhibitor Ac-DEVD-CMK, to augment mesencephalic tyrosine hydroxylase-immunoreactive (TH-ir) neuron survival in culture and following implantation into the denervated striatum of rats. We report that treatment with Ac-YVAD-CMK provided partial but nonsignificant protection for TH-ir neurons against serum withdrawal in mesencephalic cultures plated at low density, while neither caspase inhibitor promoted TH-ir neuron survival in higher density cultures, simulating graft density. We demonstrate that plating procedures (full well vs. microislands) and cell density directly affect the degree of insult experienced by TH-ir neurons following serum withdrawal. This varying degree of insult directly impacts whether caspase inhibition will augment TH-ir neuron survival. Our grafting experiments demonstrate that Ac-YVAD-CMK does not augment grafted TH-ir neuron survival when added to mesencephalic cell suspensions prior to grafting or to mesencephalic reaggregates for 3 days in vitro prior to transplantation. These experiments provide further evidence of the failure of these caspase inhibitors to augment TH-ir neuron survival. Furthermore, we suggest that cell culture paradigms used to model grafting paradigms must more closely approximate the cell densities of mesencephalic grafts to effectively screen potential augmentative treatments.
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PMID:Reassessment of caspase inhibition to augment grafted dopamine neuron survival. 1519 Nov 65

Parkinson's disease (PD) is characterized by the selective degeneration of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). A combination of genetic and environmental factors contributes to such a specific loss. Among the five PD-linked genes identified so far, parkin, a protein-ubiquitin E3 ligase, appears to be the most prevalent genetic factor in PD. Although a variety of substrates have been identified for parkin, none of them is selectively expressed in nigral DA neurons. It remains unclear how accumulation of these substrates in the absence of functional parkin may cause the selective death of DA neurons in SNpc. Here, we show that overexpression of parkin protected human DA neuroblastoma cell line (SH-SY5Y) against apoptosis induced by DA or 6-OHDA, but not by H(2)O(2) or rotenone. Parkin significantly attenuated dopamine-induced activation of c-Jun N-terminal kinase (JNK) and caspase-3. It also decreased the level of reactive oxygen species (ROS) and protein carbonyls in the cell. Inhibiting DA uptake through dopamine transporter or treating the cell with antioxidants significantly reduced oxidative stress and dopamine toxicity. Furthermore, PD-linked mutations of parkin significantly abrogated the protective effect of wild-type parkin, as well as its ability to suppress ROS and protein carbonylation. These results suggest that parkin protects against dopamine toxicity by decreasing oxidative stress and ensuing activation of apoptotic programs such as the JNK/caspase pathway. This protective function of parkin, which is greatly attenuated by its PD-linked mutations, may be uniquely important for the survival of DA neurons, as they are constantly threatened by oxyradicals produced during dopamine oxidation.
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PMID:Parkin protects human dopaminergic neuroblastoma cells against dopamine-induced apoptosis. 1519 87


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