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)

Glial activation and neuroinflammatory processes play an important role in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated glia cells can secrete various proinflammatory cytokines and neurotoxic mediators, which may influence neuronal cell survival. Recent studies have demonstrated that glia cell-mediated neuroinflammation is also related to the pathophysiology of schizophrenia. In the present study, anti-inflammatory and neuroprotective effects of antipsychotics were investigated using cultured brain cells as a model. The results showed that spiperone significantly decreased the production of nitric oxide in lipopolysaccharide-stimulated BV-2 microglia cells, primary microglia and primary astrocyte cultures. Spiperone also significantly inhibited nitric oxide production in adenosine 5'-triphosphate (ATP)-stimulated primary microglia cultures. Spiperone markedly decreased the production of tumor necrosis factor-alpha in BV-2 microglia cells. Spiperone attenuated the expression of inducible nitric oxide synthase and proinflammatory cytokines such as interleukin-1beta and tumor necrosis factor-alpha at mRNA levels in BV-2 microglia cells. Spiperone inhibited nuclear translocation and DNA binding of the p65 subunit of nuclear factor kappa B (NF-kappaB), inhibitor of kappa B (IkappaB) degradation, and phosphorylation of p38 mitogen-activated protein kinase in the lipopolysaccharide-stimulated BV-2 microglia cells. Moreover, spiperone was neuroprotective, as the drug reduced microglia-mediated neuroblastoma cell death in the microglia/neuron co-culture. These results imply that the antipsychotic spiperone has anti-inflammatory and neuroprotective effects in the central nervous system by modulating glial activation.
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PMID:The antipsychotic spiperone attenuates inflammatory response in cultured microglia via the reduction of proinflammatory cytokine expression and nitric oxide production. 1878 64

Oxidative stress plays a crucial role in the manifestations of maneb (MB) and paraquat (PQ)-induced toxicity including MB+PQ-induced Parkinson's disease (PD). Polymorphonuclear leukocytes (PMNs) actively participate in the oxidative stress-mediated inflammation and organ toxicity. The present study was undertaken to investigate the MB- and/or PQ-induced alterations in the indices of oxidative stress in rat PMNs. Animals were treated with or without MB and/or PQ in an exposure time dependent manner. In some sets of experiments, the animals were pre-treated with NOS inhibitors N(G)-nitro-L-arginine methyl ester (L-NAME) and aminoguanidine (AG) along with respective controls. A significant increase in myeloperoxidase (MPO), superoxide dismutase (SOD), nitric oxide, iNOS expression and lipid peroxidation (LPO) was observed in PMNs of MB- and/or PQ-treated animals, while catalase and glutathione S-transferase (GST) activities were attenuated. L-NAME and AG significantly reduced the augmented nitrite content, iNOS expression and MPO activity to control level in MB and PQ exposed animals. Although the augmented LPO was also reduced significantly in L-NAME and AG treated rat PMNs, the level was still higher as compared with controls. Alterations induced in SOD and GST activities were not affected by NOS inhibitors. The results thus suggest that MB and/or PQ induce iNOS-mediated nitric oxide production, which in turn increases MPO activity and lipid peroxidation, thereby oxidative stress.
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PMID:The involvement of nitric oxide in maneb- and paraquat-induced oxidative stress in rat polymorphonuclear leukocytes. 1898 85

The Lewy body is a pathological hallmark of Parkinson's disease. It has been revealed that the Lewy body contains nitrated alpha-synuclein which is prone to oligomerization. We tested the hypothesis that aging may enhance nitration of alpha-synuclein due to an exaggerated neuroinflammatory reaction such as an excessive induction of the inducible nitric oxide synthase, which occurs post-intrapallidal lipopolysaccharide (LPS) injection. Here, we show microglia activation and proinflammatory cytokine expression are more evident in the substantia nigra of elderly rats following intrapallidal LPS. In addition, greater nitration of proteins like alpha-synuclein occurs in the substantia nigra of 16-month-old rats versus 3-month-old rats, which is accompanied by a higher expression level of inducible nitric oxide synthase. These results imply that an exaggerated neuroinflammatory response that occurs with aging might be involved in the increase in prevalence of neurodegenerative diseases like Parkinson's disease.
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PMID:Aging enhances the neuroinflammatory response and alpha-synuclein nitration in rats. 1898 37

The overproduction of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) causes neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Four lignans, (+)-eudesmin (1), (+)-magnolin (2), (+)-yangambin (3) and a new structure named as epimagnolin B (4) were isolated from Magnolia fargesii (Magnoliaceae) as the inhibitors of NO production in LPS-activated microglia. The most potent compound 4 inhibited the production of NO and PGE(2) and the expression of respective enzyme iNOS and COX-2 through the suppression of I-kappaB-alpha degradation and nuclear translocation of p65 subunit of NF-kappaB.
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PMID:In vitro anti-inflammatory activity of lignans isolated from Magnolia fargesii. 1911 Apr 19

Nitric oxide (NO), which is produced from L-arginine by the nitric oxide synthase (NOS) family of enzymes, is an important second-messenger molecule that regulates several physiological functions. In endothelial cells, it relaxes smooth muscle, which decreases blood pressure. Macrophage cells produce NO as an immune defense system to destroy pathogens and microorganisms. In neuronal cells, NO controls the release of neurotransmitters and is involved in synaptogenesis, synaptic plasticity, memory function, and neuroendocrine secretion. NO is a free radical that is commonly thought to contribute to oxidative damage and molecule and tissue destruction, and thus it is somewhat surprising that it has so many significant beneficial physiological effects. However, the cell is generally protected from NO's toxic effects, except under certain pathological conditions in which excessive NO is produced. In that case, tissue damage and oxidative stress can result, leading to a wide variety of diseases, including rheumatoid arthritis, Alzheimer's disease, and Parkinson's disease, among others. In this Account, we describe research aimed at identifying small molecules that can selectively inhibit only the neuronal isozyme of NOS, nNOS. By targeting only nNOS, we attained the beneficial effects of lowering excess NO in the brain without the detrimental effects of inhibition of the two isozymes found elsewhere in the body (eNOS and iNOS). Initially, in pursuit of this goal, we sought to identify differences in the second sphere of amino acids in the active site of the isozymes. From this study, the first class of dual nNOS-selective inhibitors was identified. The moieties important for selectivity in the best lead compound were determined by structure modification. Enhancement provided highly potent, nNOS-selective dipeptide amides and peptidomimetics, which were active in a rabbit model for fetal neurodegeneration. Crystal structures of these compounds bound to NOS isozymes showed a one-amino-acid difference between nNOS and eNOS in the second sphere of amino acids; this was the difference that we were searching for from the beginning of this project. With the aid of these crystal structures, we developed a new fragment-based de novo design method called "fragment hopping", which allowed the design of a new class of nonpeptide nNOS-selective inhibitors. These compounds were modified to give low nanomolar, highly dual-selective nNOS inhibitors, which we recently showed are active in a rabbit model for the prevention of neurobehavioral symptoms of cerebral palsy. These compounds could also have general application in other neurodegenerative diseases for which excess NO is responsible.
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PMID:Design of selective neuronal nitric oxide synthase inhibitors for the prevention and treatment of neurodegenerative diseases. 1915 46

Ghrelin is an endogenous ligand for growth hormone (GH) secretagogue receptor 1a (GHS-R1a) and is produced and released mainly from the stomach. It was recently demonstrated that ghrelin can function as a neuroprotective factor by inhibiting apoptotic pathways. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes nigrostriatal dopaminergic neurotoxicity in rodents; previous studies suggest that activated microglia actively participate in the pathogenesis of Parkinson's disease (PD) neurodegeneration. However, the role of microglia in the neuroprotective properties of ghrelin is still unknown. Here we show that, in the mouse MPTP PD model generated by an acute regimen of MPTP administration, systemic administration of ghrelin significantly attenuates the loss of substantia nigra pars compacta (SNpc) neurons and the striatal dopaminergic fibers through the activation of GHS-R1a. We also found that ghrelin reduced nitrotyrosine levels and improved the impairment of rota-rod performance. Ghrelin prevents MPTP-induced microglial activation in the SNpc and striatum, the expression of pro-inflammatory molecules tumor necrosis factor alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and the activation of inducible nitric oxide synthase. The inhibitory effect of ghrelin on the activation of microglia appears to be indirect by suppressing matrix metalloproteinase-3 (MMP-3) expression in stressed dopaminergic neurons because GHS-R1a is not expressed in SNpc microglial cells. Finally, in vitro administration of ghrelin prevented 1-methyl-4-phenylpyridinium-induced dopaminergic cell loss, MMP-3 expression, microglial activation, and the subsequent release of TNF-alpha, IL-1beta, and nitrite in mesencephalic cultures. Our data indicate that ghrelin may act as a survival factor for dopaminergic neurons by functioning as a microglia-deactivating factor and suggest that ghrelin may be a valuable therapeutic agent for neurodegenerative diseases such as PD.
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PMID:Neuroprotective effect of ghrelin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease by blocking microglial activation. 1938 67

Parkinson's disease (PD) is an age- and sex-related neurodegenerative disorder of unknown aetiology. The involvement of nitric oxide synthase (NOS) in the etiopathogenesis of PD is quite well documented. We decided to examine changes in dopamine (DA) levels as well as iNOS, nNOS, eNOS mRNA and protein expression in the striatum of C57BL male and female (2- and 12-month old) mice in the course of PD-related neurodegeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The significantly decreased level of DA was previously observed in male than in female, irrespective of age. In young mice the recovery of DA was significantly greater in female compared to male mice. On the contrary, both in male and female old animals the low concentration of DA was extended up to 21 days post MPTP injection. The increases in iNOS protein expression post MPTP intoxication occurred more rapidly in male (young and old) than in female mice. The pattern of changes in iNOS protein expression was also different in young versus aged mice. nNOS protein expression increased earlier in young male than young female mice. No changes were observed in eNOS expression. In conclusion, our results support the hypothesis of the involvement of iNOS and nNOS, but not eNOS in neurodegenerative processes. Our findings suggest that age- and sex-differences in DA concentration and iNOS expression as well as sex-differences of nNOS expression after intoxication may depend on the increased susceptibility of males as well as older animals to toxic effect of MPTP and aggravated process of recovery in old brains.
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PMID:Age- and sex-differences in the nitric oxide synthase expression and dopamine concentration in the murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 1940 Nov 71

In Parkinson disease (PD), the dopaminergic (DAergic) neurons in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is still not completely understood, neuronal apoptosis and inflammation are thought to play roles. We have recently obtained evidence that matrix metalloproteinase (MMP)-3 plays a crucial role in the apoptotic signal in DAergic cells as well as activation of microglia. The present study tested whether doxycycline might modulate MMP-3 and provide neuroprotection of DAergic neurons. Doxycycline effectively suppressed the expression of MMP-3 induced in response to cellular stress in the DAergic CATH.a cells. This was accompanied by protection of CATH.a cells as well as primary cultured mesencephalic DAergic neurons via attenuation of apoptosis. The active form of MMP-3, released under the cell stress condition, was also decreased in the presence of doxycycline. In addition, doxycycline led to downregulation of MMP-3 in microglial BV-2 cells exposed to lipopolysaccharide (LPS). This was accompanied by suppression of production of nitric oxide and TNF-alpha, as well as gene expression of iNOS, TNF-alpha, IL-1beta, and COX-2. In vivo, doxycycline provided neuroprotection of the nigral DAergic neurons following MPTP treatment, as assessed by tyrosine hydroxylase immunocytochemistry and silver staining, and suppressed microglial activation and astrogliosis as assessed by Iba-1 and GFAP immunochemistry, respectively. Taken together, doxycycline showed neuroprotective effect on DAergic system both in vitro and in vivo and this appeared to derive from anti-apoptotic and anti-inflammatory mechanisms involving downregulation of MMP-3.
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PMID:Doxycycline is neuroprotective against nigral dopaminergic degeneration by a dual mechanism involving MMP-3. 1958 34

DNA damage is a proposed pathogenic factor in neurodegenerative disorders such as Parkinson disease. To probe the underpinning mechanism of such neuronal perturbation, we sought to produce an experimental model of DNA damage. We thus first assessed DNA damage by in situ nick translation and emulsion autoradiography in the mouse brain after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 4 x 20 mg/kg, ip, every 2 h), a neurotoxin known to produce a model of Parkinson disease. Here we show that DNA strand breaks occur in vivo in this mouse model of Parkinson disease with kinetics and a topography that parallel the degeneration of substantia nigra neurons, as assessed by FluoroJade labeling. Previously, nitric oxide synthase and cyclooxygenase-2 (Cox-2) were found to modulate MPTP-induced dopaminergic neuronal death. We thus assessed the contribution of these enzymes to DNA damage in mice lacking neuronal nitric oxide synthase (nNOS), inducible nitric oxide synthase (iNOS), or Cox-2. We found that the lack of Cox-2 and nNOS activities but not of iNOS activity attenuated MPTP-related DNA damage. We also found that not only nuclear, but also mitochondrial, DNA is a target for the MPTP insult. These results suggest that the loss of genomic integrity can be triggered by the concerted actions of nNOS and Cox-2 and provide further support to the view that DNA damage may contribute to the neurodegenerative process in Parkinson disease.
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PMID:Neuronal NOS and cyclooxygenase-2 contribute to DNA damage in a mouse model of Parkinson disease. 1961 17

Oxidative stress is regarded as a mediator of nerve cell death in several neurodegenerative disorders, such as Parkinson's disease. Sesamin, a lignan mainly found in sesame oil, is currently under study for its anti-oxidative and possible neuroprotective properties. We used 1-methyl-4-phenyl-pyridine (MPP(+)) ion, the active metabolite of the potent parkinsonism-causing toxin 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, to produce oxidative stress and neurodegeneration in neuronal PC12 cells, which express dopamine, as well as neurofilaments. Our results show that picomolar doses of sesamin protected neuronal PC12 cells from MPP(+)-induced cellular death, as revealed by colorimetric measurements and production of reactive oxygen species. We also demonstrated that sesamin acted by rescuing tyrosine hydroxylase levels from MPP(+)-induced depletion. Sesamin, however, did not modulate dopamine transporter levels, and estrogen receptor-alpha and -beta protein expression. By examining several parameters of cell distress, we found that sesamin also elicited a strong increase in superoxide dismutase activity as well as protein expression and decreased catalase activity and the MPP(+) stimulated inducible nitric oxide synthase protein expression, in neuronal PC12 cells. Finally, sesamin possessed significant anti-inflammatory properties, as disclosed by its potential to reduce MPP(+)-induced interleukin-6 mRNA levels in microglia. From these studies, we determined the importance of the lignan sesamin as a neuroprotective molecule and its possible role in complementary and/or preventive therapies of neurodegenerative diseases.
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PMID:Sesamin modulates tyrosine hydroxylase, superoxide dismutase, catalase, inducible NO synthase and interleukin-6 expression in dopaminergic cells under MPP+-induced oxidative stress. 1979 9


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