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)

Mitochondria are the specialized organelles for energy metabolism but also participate in the production of O(2) active species, cell cycle regulation, apoptosis and thermogenesis. Classically, regulation of mitochondrial energy functions was based on the ADP/ATP ratio, which dynamically stimulates the transition between resting and maximal O(2) uptake. However, in the last years, NO was identified as a physiologic regulator of electron transfer and ATP synthesis by inhibiting cytochrome oxidase. Additionally, NO stimulates the mitochondrial production of O(2) active species, primarily O(2)(-) and H(2)O(2), and, depending on NO matrix concentration, of ONOO(-), which is responsible for the nitrosylation and nitration of mitochondrial components. By this means, alteration in mitochondrial complexes restricts energy output, further increases O(2) active species and changes cell signaling for proliferation and apoptosis through redox effects on specific pathways. These mechanisms are prototypically operating in prevalent generalized diseases like sepsis with multiorgan failure or limited neurodegenerative disorders like Parkinson's disease. Complex I appears to be highly susceptible to ONOO(-) effects and nitration, which defines an acquired group of mitochondrial disorders, in addition to the genetically induced syndromes. Increase of mitochondrial NO may follow over-expression of nNOS, induction and translocation of iNOS, and activation and/or increased content of the newly described mtNOS. Likewise, mtNOS is important in the modulation of O(2) uptake and cell signaling, and in mitochondrial pathology, including the effects of aging, dystrophin deficiency, hypoxia, inflammation and cancer.
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PMID:Nitric oxide, complex I, and the modulation of mitochondrial reactive species in biology and disease. 1505 22

Neuronal damage following stroke or neurodegenerative diseases is thought to stem in part from overexcitation of N -methyl-D-aspartate (NMDA) receptors by glutamate. NMDA receptors triggered neurotoxicity is mediated in large part by activation of neuronal nitric oxide synthase (nNOS) and production of nitric oxide (NO). Simultaneous production of superoxide anion in mitochondria provides a permissive environment for the formation of peroxynitrite (ONOO-). Peroxynitrite damages DNA leading to strand breaks and activation of poly(ADP-ribose) polymerase-1 (PARP-1). This signal cascade plays a key role in NMDA excitotoxicity, and experimental models of stroke and Parkinson's disease. The mechanisms of PARP-1-mediated neuronal death are just being revealed. While decrements in ATP and NAD are readily observed following PARP activation, it is not yet clear whether loss of ATP and NAD contribute to the neuronal death cascade or are simply a biochemical marker for PARP-1 activation. Apoptosis-inducing factor (AIF) is normally localized to mitochondria but following PARP-1 activation, AIF translocates to the nucleus triggering chromatin condensation, DNA fragmentation and nuclear shrinkage. Additionally, phosphatidylserine is exposed and at a later time point cytochrome c is released and caspase-3 is activated. In the setting of excitotoxic neuronal death, AIF toxicity is caspase independent. These observations are consistent with reports of biochemical features of apoptosis in neuronal injury models but modest to no protection by caspase inhibitors. It is likely that AIF is the effector of the morphologic and biochemical events and is the commitment point to neuronal cell death, events that occur prior to caspase activation, thus accounting for the limited effects of caspase inhibitors. There exists significant cross talk between the nucleus and mitochondria, ultimately resulting in neuronal cell death. In exploiting this pathway for the development of new therapeutics, it will be important to block AIF translocation from the mitochondria to the nucleus without impairing important physiological functions of AIF in the mitochondria.
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PMID:Deadly conversations: nuclear-mitochondrial cross-talk. 1537 59

We examined the effects of perindopril on the dopaminergic system in mice after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treatment. The mice received four intraperitoneal injections of MPTP at 1-h intervals. Administration of perindopril showed dose-dependent neuroprotective effects against striatal dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion 3 days after MPTP treatment. Our immunohistochemical study showed that MPTP can severe damage in tyrosine hydroxylase (TH)-immunoreactive neurons after MPTP treatment. The administration of perindopril significantly attenuated MPTP-induced substantia nigra and striatal damage. The present study also showed that the immunoreactivity of parvalbumin (PV)- or neuronal nitric oxide synthase (nNOS)-positive cells in the substantia nigra was decreased 7 days after MPTP treatment, whereas no significant changes were observed in these cells of the striatum throughout the experiments. The administration of perindopril significantly attenuated MPTP-induced decrease of the PV- or nNOS-immunoreactivity in the nigral cells. In double-labeled immunostaining with anti-PV and anti-nNOS antibody, PV-immunoreactive cell bodies and fibers were not double-labeled for nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra after MPTP treatment. Furthermore, PV- or nNOS-immunoreactive cell bodies and fibers in both the striatum and substantia nigra were not double-labeled for TH-immunoreactive cell bodies and fibers. These results demonstrate that the ACE inhibitor perindopril has a dose-dependent protective effect against MPTP-induced striatal dopamine, DOPAC and HVA depletion in mice. The present study also demonstrates that perindopril is effective against MPTP-induced degeneration of the nigral neurons and interneurons. Furthermore, our immunohistochemical study suggests that PV-immunoreactive cells and nNOS-immunoreactive cells are different interneurons in both the striatum and substantia nigra. Thus, our results provide further evidence that the ACE inhibitor perindopril may offer a novel therapeutic strategy for Parkinson's disease (PD).
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PMID:Effect of angiotensin-converting enzyme inhibitor perindopril on interneurons in MPTP-treated mice. 1557 74

In this study, we investigated the molecular mechanism of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes parkinsonism in experimental animals and humans. Using wild-type and human neuronal nitric oxide synthase (nNOS) stably transfected neuroblastoma cells (SH-SY5Y), we showed that nNOS overexpression in SH-SY5Y cells greatly enhanced proteasome activity and mitigated MPP+-induced apoptosis. During MPP+-induced oxidative stress, intracellular BH4 levels decreased, resulting in nNOS "uncoupling" (i.e., switching from nitric oxide to superoxide generation). Increasing the intracellular BH4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells. Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed.
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PMID:Sepiapterin attenuates 1-methyl-4-phenylpyridinium-induced apoptosis in neuroblastoma cells transfected with neuronal NOS: role of tetrahydrobiopterin, nitric oxide, and proteasome activation. 1619 33

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes the damage of dopaminergic neurons as seen in Parkinson's disease. Oxidative stress has been as one of several pathogenic hypotheses for Parkinson's disease. Here we investigated whether arundic acid, an astrocyte-modulating agent, can protect against alterations of nitric oxide synthase (NOS) and superoxide dismutase (SOD) expression on MPTP neurotoxicity in mice, utilizing an immunohistochemistry. For this purpose, anti-tyrosine hydroxylase (TH) antibody, anti-dopamine transporter (DAT) antibody, anti-Cu/Zn-SOD antibody, anti-Mn-SOD antibody, anti-nNOS antibody, anti-eNOS antibody and anti-iNOS antibody were used. The present study showed that the arundic acid had a protective effect against MPTP-induced neuronal damage in the striatum and substantia nigra of mice. The protective effect may be, at least in part, caused by the reductions of the levels of reactive nitrogen (RNS) and oxygen species (ROS) against MPTP neurotoxicity. These results suggest that the pharmacological modulation of astrocyte may offer a novel therapeutic strategy for the treatment of Parkinson's disease. Furthermore, our results provide further evidence that a combination of nNOS inhibitors, iNOS inhibitors and free radical scavengers may be effective in the treatment of neurodegenerative diseases. Thus our present results provide valuable information for the pathogenesis of degeneration of the nigrostriatal dopaminergic neuronal pathway.
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PMID:Neuroprotective effect of arundic acid, an astrocyte-modulating agent, in mouse brain against MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) neurotoxicity. 1630 47

There are a number of reasons for believing that nitric oxide participates in motor control in the striatum. Therefore, effects of neuronal nitric oxide synthase inhibitor 7-nitroindazole (7-NI) were studied on the reserpine model of Parkinson's disease in Swiss and C57BL/6 mice using the open-field test. Mice received reserpine (1 mg/kg administered intraperitoneally). A significant hypolocomotion was observed 24 h and 48 h after reserpine injection. The treatment with 7-nitroindazole (25 mg/kg, administered intraperitoneally, 30 min after reserpine) attenuated reserpine-induced hypolocomotion 24 h and 48 h after the treatment in Swiss mice, but not completely in C57BL/6 mice. These results suggest that nitric oxide functions as an intercellular messenger in motor circuits in the brain. Moreover, our data suggests that the comparison of such mouse strains may provide information on genetic basis for strain differences in different sensitivity to these drugs.
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PMID:Different effects of 7-nitroindazole in reserpine-induced hypolocomotion in two strains of mice. 1654 64

Mechanisms of neuronal cell death in apoptosis and necrosis are examined. Neurotoxic processes underlying cellular destruction may involve N-methyl-D-aspartate (NMDA) receptor activation and/or activation of neuronal nitric oxide synthase but the depletion of energy and generation of free radicals appears to be critical. In Alzheimer's disease the damaging effects of peroxynitrite and exposure to beta-amyloid peptide is evident. Mitochondrial dysfunction is involved in several neurodegenerative diseases including Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease as well as Alzheimer's disease and in these disorders the innovations offered by techniques ranging from transgenic mouse models of the disorder to cell culture preparations are remarkable. Agents of neuroprotection and neurorestoration possess either characteristics specific to particular disorders or have a general applicability or both. The vast array of agents available are for the most part the objectives of laboratory examinations but an increasing selection of compounds are reaching the clinical necessities thereby influencing current strategic notions to modify tactical contingencies. Among the agents listed are included: inhibitors of the enzyme poly-ADP-ribose polymerase, inhibition of apoptotic cell death, agents acting on mitochondrial permeability transition, excitatory amino acid antagonists, applications of neurotrophins, immunophilins, agents influencing heme oxygenase-1 expression and iron sequestration in aging astroglia, improvements in mitochondrial energy production or buffering, and finally dopaminemimetics with differential affinities for dopamine receptors.
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PMID:Neuroprotective and neurorestorative strategies for neuronal injury. 1678 33

Nitric oxide synthases (NOS) and mitochondrial DNA-polymorphisms have been associated with the risk of developing Parkinson's disease (PD). In this report, we genotyped 450 PD-patients and 200 controls for three polymorphisms in the endothelial, inducible and neuronal NOS-genes, and for the T4336C and A10398G mitochondrial DNA-polymorphisms. None of the eNOS (intron 4 VNTR), iNOS (exon 22 A/G), or nNOS (exon 29T/C) were significantly associated with PD. Mitochondrial 4336C increased the PD-risk among women (OR=6.13), while the 10398G had a protective effect (OR=0.52). We did not find significantly interactions between the NOS and mitochondrial polymorphisms in the risk for PD in our population.
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PMID:No association between Parkinson's disease and three polymorphisms in the eNOS, nNOS, and iNOS genes. 1717 75

The neuropathological hallmark of Parkinson's disease (PD) is the selective degeneration of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNc). In this study, using a microdialysis technique, we investigated whether an inhibitor of neuronal nitric oxide synthase (nNOS), 7-nitrindazole (7-NI), could protect against DAergic neuronal damage induced by in vivo infusion of 1-methyl-4-phenylpiridinium iodide (MPP(+)) in freely moving rats. Experiments were performed over 2 days in three groups of rats: (a) nonlesioned, (b) MPP(+)-lesioned, and (c) 7-NI pretreated MPP(+)-lesioned rats. On day 1, control rats were perfused with an artificial CSF, while 1 mM MPP(+) was infused into the striatum for 10 min in the other two groups. The infusion of the MPP(+) produced a neurotoxic damage of the SNc DA neurons and increased striatal DA levels. On day 2, 1 mM MPP(+) was reperfused for 10 min into the striata of each rat group and DA levels were measured as an index of neuronal cell integrity. The limited rise of DA following MPP(+) reperfusion in the MPP(+)-lesioned rats was due to toxin-induced neuronal loss and was reversed by pretreatment with 7-NI (50 mg/kg, intraperitoneally) on day 1, indicating a neuroprotective effect by inhibiting NO formation. These results indicate that neuronally derived NO partially mediates MPP(+)-induced neurotoxicity. The similarity between the MPP(+) model and PD suggests that NO may play a significant role in its etiology.
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PMID:7-nitroindazole protects striatal dopaminergic neurons against MPP+-induced degeneration: an in vivo microdialysis study. 1726 89

The role that nitric oxide may play in modulating graft function in long-term fetal ventral mesencephalic grafts in an animal model of Parkinson's disease was investigated. Mature grafts harvested from the entire fetal ventral mesencephalon possessed a large number of neuronal nitric oxide synthase (nNOS)/NADPH-diaphorase-containing neurons throughout the graft intermingled with dopaminergic neurons. The morphological and neurochemical characteristics of these NADPH-diaphorase neurons resembled those in centers adjacent to the substantia nigra of adult brain but not that of the striatum. Pretreatment with the nNOS blocker, 7-nitroindazole, resulted in contralateral rotations following methamphetamine challenge in long-term grafted animals that previously showed normalized rotational behavior. In contrast, mature grafts derived from fetal ventral mesencephalon without the midline areas possessed only a few nNOS-containing neurons within the grafts, and a similar methamphetamine challenge following 7-nitroindazole pretreatment in long-term grafted rats that previously showed normalized rotational behavior resulted in random movements. Our results indicate that nitric oxide-containing neurons inadvertently included during grafting may affect graft function, and excluding the midline areas of the ventral mesencephalon during tissue harvesting may minimize this effect.
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PMID:Nitric oxide-containing neurons in long-term grafts in a rat model of Parkinson's disease. 1770 35


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