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

The expression of early response gene proteins c-Fos, c-Jun, and GAP-43 and their association with 6-hydroxydopamine (6-OHDA)-mediated oxidative injury were investigated using catecholaminergic PC12 cell line. Significant induction in the expression of c-Fos (P < 0.01), c-Jun (P < 0.001) and GAP-43 (P < 0.05) was observed following 2 h exposure to 6-OHDA (10(-6) M), which persisted during 24 h of observation. The exposed cells exhibited an increase in lipid peroxidation (48, 59 and 33%) along with decreased catalase activity (49, 30 and 13%) and glutathione levels (39, 28 and 16%) following 24, 48 and 72 h exposure, respectively. A concentration-dependent functional impairment of mitochondria as studied by 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and decreased cell survival were also observed following 6-OHDA (10(-4), 10(-5) M) exposure for 24, 48 and 72 h. The results indicate a role of the early response gene in oxidative stress-mediated dopaminergic cell death by 6-OHDA. Similar mechanisms may also be operative in the development of Parkinson's disease, as an increased presence/formation of endogenous 6-OHDA has been reported in Parkinson's patients.
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PMID:Induced expression of early response genes/oxidative injury in rat pheochromocytoma (PC12) cell line by 6-hydroxydopamine: implication for Parkinson's disease. 1221 41

In neuronal stress and degeneration, mitogen-activated protein (MAP) kinase signaling pathways play an important role. We studied the pattern of activation of the c-Jun N terminal kinase (JNK) signal transduction pathway during the course of a subacute MPTP mouse model of Parkinson's disease. In this model, there was no significant neuronal loss, but the function of the dopaminergic neurons was significantly decreased. During MPTP administration, phosphorylation of p-Jun was increased in the substantia nigra, and MKK4 was increased both in the striatum and substantia nigra. We conclude that after MPTP intoxication in the mouse, activation of the JNK pathway occurs both in the striatum and in the substantia nigra. This activation does not seem to corrrelate with loss of neuronal cell bodies but might represent a response to damage/loss of axonal terminals.
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PMID:Activation of the c-Jun N terminal kinase pathway in an animal model of Parkinson's disease. 1248 68

Apoptosis has been proposed as a mechanism of cell death in Alzheimer's, Huntington's and Parkinson's diseases and the occurrence of apoptosis in these disorders suggests a common mechanism. Events such as oxidative stress, calcium toxicity, mitochondria defects, excitatory toxicity, and deficiency of survival factors are all postulated to play varying roles in the pathogenesis of the diseases. However, the transcription factor c-jun may play a role in the pathology and cell death processes that occur in Alzheimer's disease. Parkinson's disease (PD) is also a progressive disorder involving the specific degeneration and death of dopamine neurons in the nigrostriatal pathway. In Parkinson's disease, dopaminergic neurons in the substantia nigra are hypothesized to undergo cell death by apoptotic processes. The commonality of biochemical events and pathways leading to cell death in these diseases continues to be an area under intense investigation. The current therapy for PD and AD remains targeting replacement of lost transmitter, but the ultimate objective in neurodegenerative therapy is the functional restoration and/or cessation of progression of neuronal loss. This chapter will describe a novel approach for the treatment of neurodegenerative diseases through the development of kinase inhibitors that block the active cell death process at an early transcriptional independent step in the stress activated kinase cascade. In particular, preclinical data will be presented on the c-Jun Amino Kinase pathway inhibitor, CEP-1347/KT-7515, with respect to it's properties that make it a desirable clinical candidate for treatment of various neurodegenerative diseases.
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PMID:Discovery of CEP-1347/KT-7515, an inhibitor of the JNK/SAPK pathway for the treatment of neurodegenerative diseases. 1251 22

Genes associated with Parkinson's disease (PD) have suggested a role for ubiquitin-proteasome dysfunction and aberrant protein degradation in this disorder. Inasmuch as oxidative stress has also been implicated in PD, the present study examined transcriptional changes mediated by the Parkinsonism-inducing neurotoxins 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenylpyridinium (MPP+) in a dopaminergic cell line. Microarray analysis of RNA isolated from toxin treated samples revealed that the stress-induced transcription factor CHOP/Gadd153 was dramatically up-regulated by both 6-OHDA and MPP+. Treatment with 6-OHDA also induced a large number of genes involved in endoplasmic reticulum stress and unfolded protein response (UPR) such as ER chaperones and elements of the ubiquitin-proteasome system. Reverse transcription-PCR, Western blotting, and immunocytochemical approaches were used to quantify and temporally order the UPR pathways involved in neurotoxin-induced cell death. 6-OHDA, but not MPP+, significantly increased hallmarks of UPR such as BiP, c-Jun, and processed Xbp1 mRNA. Both toxins increased the phosphorylation of UPR proteins, PERK and eIF2 alpha, but only 6-OHDA increased phosphorylation of c-Jun. Thus, 6-OHDA is capable of triggering multiple pathways associated with UPR, whereas MPP+ exhibits a more restricted response. The involvement of UPR in these widely used neurotoxin models supports the role of ubiquitin-proteasome pathway dysfunction in PD.
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PMID:Parkinsonian mimetics induce aspects of unfolded protein response in death of dopaminergic neurons. 1259 33

Neurodegenerative diseases remain a huge unmet pharmaceutical need. For some diseases such as Parkinson's disease, there are currently only palliative therapies, and for others such as Alzheimer's disease there are no proven therapies on the market that have any significant impact on disease progression. Recent work has suggested that cell death may play a key role in a number of neurodegenerative diseases, and halting this aberrant cell death may halt disease progression. Kinases identified in cell death pathways may be attractive targets for neurodegenerative diseases. In this review, the authors will focus on three families of related mitogen-activated protein kinases (MAPKs), namely, the extracellular signal-regulated protein kinases (ERKs), the c-Jun N-terminal kinases (JNKs) and the p38 MAPKs. The evidence for activation of each of these pathways in disease states and in models of neurodegenerative disorders will be examined. Effects of inhibitors, where available, will be discussed, and potential problems and side effects of kinase inhibitors as therapeutics will be addressed.
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PMID:MAPKs: new targets for neurodegeneration. 1266 97

SH-SY5Y neuroblastoma cells exposed to the complex I inhibitor/parkinsonian neurotoxin methylpyridinium ion (MPP(+)) activate both survival and death-promoting signaling pathways and undergo MEK/ERK-dependent, phosphatidylinositol-3 kinase-dependent, and c-Jun kinase-dependent cell death. Because genomic responses to MPP(+) are not extensively characterized, we used nylon cDNA arrays to measure gene expression following exposure to an apoptosis-producing [MPP(+)]. Many changes occurred within 5 min, and all gene expression changes appeared before biochemical and morphological markers of apoptosis. The majority of gene expression changes in SY5Y were not found in rho(0) cells, indicating dependence of these changes on intact electron transport activity. rho(0) cells exposed to MPP(+) produced different expression profiles, indicating the potential for responses independent of complex I inhibition. MPP(+)-induced gene expression patterns in normal SY5Y cells were sensitive to inhibitors of MEK/ERK (UO 126) or phosphatidylinositol-3 kinase (LY 294002), demonstrating regulation of gene expression by these survival-promoting signaling pathways. The primary signaling molecules mediating these MPP(+)-induced gene expression changes are unknown but ultimately utilize MEK/ERK and phosphatidylinositol-3 kinase signaling. Genes suppressed by UO 126 or LY 294002 during MPP(+) exposure may mediate cell survival; those expressed in the presence of UO 126 or LY 294002 may mediate cell death in this in vitro model of Parkinson's disease.
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PMID:Dependence on electron transport chain function and intracellular signaling of genomic responses in SH-SY5Y cells to the mitochondrial neurotoxin MPP(+). 1271 Sep 31

Nitric oxide (NO), in excess, behaves as a cytotoxic substance mediating the pathological processes that cause neurodegeneration. The NO-induced dopaminergic cell loss causing Parkinson's disease (PD) has been postulated to include the following: an inhibition of cytochrome oxidase, ribonucleotide reductase, mitochondrial complexes I, II, and IV in the respiratory chain, superoxide dismutase, glyceraldehyde-3-phosphate dehydrogenase; activation or initiation of DNA strand breakage, poly(ADP-ribose) synthase, lipid peroxidation, and protein oxidation; release of iron; and increased generation of toxic radicals such as hydroxyl radicals and peroxynitrite. NO is formed by the conversion of L-arginine to L-citrulline by NO synthase (NOS). At least three NOS isoforms have been identified by molecular cloning and biochemical studies: a neuronal NOS or type 1 NOS (nNOS), an immunologic NOS or type 2 NOS (iNOS), and an endothelial NOS or type 3 NOS (eNOS). The enzymatic activities of eNOS or nNOS are induced by phosphorylation triggered by Ca(2+) entering cells and binding to calmodulin. In contrast, the regulation of iNOS seems to depend on de novo synthesis of the enzyme in response to a variety of cytokines, such as interferon-gamma and lipopolysaccharide. The evidence that NO is associated with neurotoxic processes underlying PD comes from studies using experimental models of this disease NOS inhibitors can prevent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Furthermore, NO fosters dopamine depletion, and the said neurotoxicity is averted by nNOS inhibitors such as 7-nitroindazole working on tyrosine hydroxylase-immunoreactive neurons in substantia nigra pars compacta. Moreover, mutant mice lacking the nNOS gene are more resistant to MPTP neurotoxicity when compared with wild-type littermates. Selegiline, an irreversible inhibitor of monoamine oxidase B, is used in PD as a dopaminergic function-enhancing substance. Selegiline and its metabolite, desmethylselegiline, reduce apoptosis by altering the expression of a number of genes, for instance, superoxide dismutase, Bcl-2, Bcl-xl, NOS, c-Jun, and nicotinamide adenine nucleotide dehydrogenase. The selegiline-induced antiapoptotic activity is associated with prevention of a progressive reduction of mitochondrial membrane potential in preapoptotic neurons. As apoptosis is critical to the progression of neurodegenerative disease, including PD, selegiline or selegiline-like compounds to be discovered in the future may be efficacious in treating PD.
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PMID:Peroxynitrite and mitochondrial dysfunction in the pathogenesis of Parkinson's disease. 1288 Apr 86

Parkinson's disease (PD) is a neurodegenerative disorder characterized by loss of dopamine-containing neurons, but the molecular pathways underlying its pathogenesis remain uncertain. Here, we show that by eliminating c-Jun N-terminal kinases (JNKs) we can prevent neurodegeneration and improve motor function in an animal model of PD. First, we found that c-Jun is activated in dopaminergic neurons from PD patients and in the 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine (MPTP) mouse model of PD. Examination of various JNK-deficient mice shows that both JNK2 and JNK3, but not JNK1, are required for MPTP-induced c-Jun activation and dopaminergic cell demise. Furthermore, we have identified cyclooxygenase (COX) 2 as a molecular target of JNK activation and demonstrated that COX-2 is indispensable for MPTP-induced dopaminergic cell death. Our data revealed that JNK2- and JNK3-induced COX-2 may be a principle pathway responsible for neurodegeneration in PD.
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PMID:JNK-mediated induction of cyclooxygenase 2 is required for neurodegeneration in a mouse model of Parkinson's disease. 1470 77

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in Parkinson's disease (PD) model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In order to study roles of JNK activity in neuronal apoptosis in this model, we blocked JNK activity in vivo using a specific inhibitor of JNK, SP600125. Our data showed that MPTP-induced phospho-c-Jun of substantial nigral neurons, caused apoptosis of dopaminergic neurons, and decreased the dopamine level in striatal area. We found that inhibiting JNK with SP600125 reduced the levels of c-Jun phosphorylation, protected dopaminergic neurons from apoptosis, and partly restored the level of dopamine in MPTP-induced PD in C57BL/6N mice. These results indicate that JNK pathway is the major mediator of the neurotoxic effects of MPTP in vivo and inhibiting JNK activity may represent a new and effective strategy to treat PD.
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PMID:SP600125, a new JNK inhibitor, protects dopaminergic neurons in the MPTP model of Parkinson's disease. 1474 94

Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.
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PMID:Rotenone-induced apoptosis is mediated by p38 and JNK MAP kinases in human dopaminergic SH-SY5Y cells. 1497 42


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