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)

Microglia are innate immune cells in the central nervous system. Activation of microglia plays an important role in the processes of several neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, and HIV dementia. Activated microglia can produce various proinflammatory cytokines and nitric oxide (NO), which may exert neurotoxic effects. Inhibition of microglia activation may alleviate neurodegeneration under these conditions. To search for the novel therapeutic agents against neuroinflammatory diseases, we have screened a series of flavonoid compounds using a cell-based assay. Our studies showed that fisetin markedly suppressed the production of tumor necrosis factor (TNF)-alpha, NO, and prostaglandin (PG) E2 in lipopolysaccharide (LPS)-stimulated BV-2 microglia cells or primary microglia cultures. Fisetin also inhibited the gene expression of TNF-alpha, interleukin (IL)-1 beta, cyclooxygenase (COX-2) and inducible nitric oxide synthase (iNOS) at both mRNA and protein levels. Fisetin significantly suppressed I kappa B degradation, nuclear translocation of NF-kappa B, and phosphorylation of p38 mitogen-activated protein kinase (MAPKs) in the LPS-stimulated BV-2 microglia cells. In addition, fisetin reduced cytotoxicity of LPS-stimulated microglia toward B35 neuroblastoma cells in a co-culture system. These results indicate that fisetin has a strong anti-inflammatory activity in brain microglia, and could be a potential therapeutic agent for the treatment of neuroinflammatory diseases.
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PMID:Suppressive effects of flavonoid fisetin on lipopolysaccharide-induced microglial activation and neurotoxicity. 1827 3

Alzheimer's disease (AD) and Parkinson's disease (PD) are two of the most significant neurodegenerative disorders in the developed world. However, although these diseases were described almost a century ago, the molecular mechanisms that lead to the neuronal cell death associated with these diseases are not yet clear, and vigorous research efforts have failed to identify effective treatment options. In the present review, we evaluate the potential mechanisms underlying apoptosis and neuronal death in neurodegenerative disorders. A role for mitochondria in the release of proapoptotic proteins, such as cytochrome c and apoptosis-inducing factor (AIF) etc., is discussed along with key processes involving oxidative stress and activation of glutamate receptors. We also deliberate the implication of DNA damage, primarily p53 induction and reentry in the cell cycle. Finally, we postulate that multitargeting therapies comprising antioxidants, cell cycle inhibitors and modulating agents of COX-2 or c-JUN kinase pathways could be suitable strategies to prevent or delay the process of neuronal cell death in neurodegenerative disorders. Thus, the aim of this review is to discuss the pathways involved in the pathogenesis of neurodegenerative diseases such as AD, PD and Huntington's disease (HD). Furthermore, current and future pharmacotherapeutics will be considered.
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PMID:Apoptotic mechanisms involved in neurodegenerative diseases: experimental and therapeutic approaches. 1838 97

Cyclooxygenase (COX) is the rate-limiting enzyme that catalyzes the formation of prostaglandins from arachidonic acid. The inducible isoform COX-2 is upregulated in the dopaminergic neurons of the substantia nigra of postmortem Parkinson's disease (PD) patients and in neurotoxin-induced Parkinsonism models. COX-2 has attracted significant attention as an important source of oxidative stress in dopaminergic neurons due to its potential to oxidize catechols including dopamine. However, the role of COX-2 in the pathogenesis of PD has not been fully evaluated. Here, we show that COX-2 induces dopamine oxidation, as evidenced by the findings that COX-2 can facilitate dopamine oxidation in a cell-free system and in COX-2-overexpressing SH-SY5Y cells, and that this can be completely abolished by the selective COX-2 inhibitor meloxicam. Increased COX-2 expression causes oxidative protein modification and alpha-synuclein accumulation in dopaminergic cells. These data suggest that an abnormal increase in COX-2 expression causes dopamine oxidation and contributes to the preferential vulnerability of dopaminergic cells as in PD.
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PMID:Cyclooxygenase-2 is involved in oxidative damage and alpha-synuclein accumulation in dopaminergic cells. 1840 18

Parkinson's disease (PD) clinical features comprise both motor and nonmotor manifestations. Among the nonmotor complications, dementia is the most important. Approximately 40% of PD patients are affected by cognitive impairment. Remarkably, in addition to age, dementia is an independent predictor of mortality, whereas age at onset of PD and severity of neurological symptoms are not. In this review, I summarize the current knowledge of the pathogenesis of the PD cognitive impairment in relation to the therapies presently accessible and those that could become strategic in the near future. It is hypothesized that patients with PD show two components of cognitive dysfunction (CD): a generalized profile of subcortical dementia (PDsCD), and an overlapped pattern suggesting specific prefrontal damage with CD (PDpFCD). PDsCD is associated with structural neocortical/subcortical changes in the brain (in frontal, parietal, limbic, and temporal lobes, as well as in midbrain structures). In PDpFCD cognitive deficits comprise impairments in neuropsychological tests sensitive for frontal lobe function (discrete elements of episodic and working memory for instance), which are considered to be the consequence of dysfunction in neuronal loops connecting the prefrontal cortex and basal ganglia. Drugs reviewed for targeting PDsCD include: cholinesterase inhibitors, agents with mixed cholinergic and dopaminergic properties, antiglutamatergic drugs, mixed antiglutamatergic/dopaminergic agents; antioxidants and enhancers of mitochondrial functions, and anti-COX-2, as well as other anti-inflammatory mediators. Preliminary studies with vehicles that may target PDpFCD include piribedil, tolcapone, amantadine, and farampator. Additional agents (citicoline and neuroimmuniphilines, among others) will be outlined. A brief overview on neuroprotection and promising new biological advances in PD (deep brain stimulation, stem cells, gene therapy) also will be summarized.
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PMID:Current management of the cognitive dysfunction in Parkinson's disease: how far have we come? 1853 72

Anti-inflammatory drugs such as ibuprofen appear to prevent the development of Parkinson's disease (PD); however, long-term use has undesirable side-effects. A new strategy for anti-inflammatory drug therapy is using a dual inhibitor of COX and lipooxygenase (LOX). Here, we compared the dopaminergic neuroprotective property of phenidone (a dual COX and LOX inhibitor) with COX or LOX inhibitors including SC-560 (a COX-1 inhibitor), aspirin (a COX-1/2 inhibitor), meloxicam (a preferential COX-2 inhibitor), caffeic acid (a 5-LOX inhibitor), and esculetin (a 5, 12-LOX inhibitor) in our lipopolysaccharide (LPS)-induced PD animal model. Our results show that COX-2 and 5-LOX play a major role in LPS-induced dopaminergic neurotoxicity, as meloxicam and phenidone attenuated LPS-induced oxidative stress and meloxicam, phenidone, and caffeic acid attenuated dopaminergic neurodegeneration, while SC-560, aspirin, and esculetin did not. In addition, phenidone was superior in attenuating LPS-induced dopaminergic neurodegeneration and microglia activation, probably as a result of dual inhibition of COX-2 and LOX. Therefore, dual inhibition of COX and LOX with phenidone represents a promising new candidate for anti-inflammatory drug therapy, and may provide a novel therapeutic approach for inflammation-related neurodegenerative diseases including PD.
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PMID:Phenidone protects the nigral dopaminergic neurons from LPS-induced neurotoxicity. 1876 Mar 29

In this study, we investigated the neuroprotective effect of a benzylideneacetophenone derivative, JC3, in a mouse model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD). C57BL/6 mice were treated with MPTP (30 mg/kg, i.p.) for 5 consecutive days. JC3 (10 mg/kg, i.p.) treatment was initiated 2 h after the first administration of MPTP and then at 24-h intervals for 3 consecutive days. The mice were sacrificed for analyses 7 days after the last MPTP injection. Immunohistochemistry and Western blot were used to determine the expression levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), OX-42 (a marker of microglial activation), and glial fibrillary acid protein (GFAP, a marker of astrocyte activation) in the substantia nigra (SN) and striatum (ST). The results of these experiments demonstrated that JC3 restored the decreased TH-immunoreactivity (IR) and DAT and JC3 attenuated the increase in OX-42, GFAP, and COX-2 on the SN and ST on day 7 post-MPTP injection. These results suggest that JC3 can be a neuroprotective agent in an MPTP-induced model of PD.
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PMID:Neuroprotective effect of benzylideneacetophenone derivative on the MPTP model of neurodegeneration in mice. 1880 51

The present study was undertaken to investigate the neuroprotective effects of resveratrol on 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease in rats. 6-OHDA-induced Parkinson's disease rat model involves chronic inflammation, mitochondrial dysfunction, and oxidative stress, and the loss of the dopaminergic neurons in the substantia nigra is the predominant lesion. Resveratrol has been shown to have anti-inflammatory actions, and thus was tested for its beneficial effects using 6-OHDA-induced Parkinson's disease rat model. Adult Sprague-Dawley (SD) rats were unilaterally injected with 6-OHDA (5 microg/2 microl) into the right striatum, and the striatum damage was assessed by rotational test, ultrahistopathology, and molecular alterations. Resveratrol (10, 20 and 40 mg/kg) was then given orally to Parkinson's disease rats, daily for 10 weeks to examine the protective effects. Rotational test (turns of rats) showed that resveratrol significantly attenuated apomorphine-induced turns of rats in 6-OHDA-injuried Parkinson's disease rat model as early as two weeks of administration. Ultrastructural analysis showed that resveratrol alleviated 6-OHDA-induced chromatin condensation, mitochondrial tumefaction and vacuolization of dopaminergic neurons in rat substantia nigra. Furthermore, resveratrol treatment also significantly decreased the levels of COX-2 and TNF-alpha mRNA in the substantia nigra as detected by real-time RT-PCR. COX-2 protein expression in the substantia nigra was also decreased as evidenced by Western blotting. These results demonstrate that resveratrol exerts a neuroprotective effect on 6-OHDA-induced Parkinson's disease rat model, and this protection is related to the reduced inflammatory reaction.
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PMID:Neuroprotective effect of resveratrol on 6-OHDA-induced Parkinson's disease in rats. 1894 Jan 89

Parkinson's disease (PD) is a degenerative neurodopaminergic disease in nigrostriatum pathway of human and is responsible for most of the movement disorders. Increasing evidence suggests that an inflammatory reaction accompanies the pathological processes caused by Cyclooxygenase (COX) seen in many neurodegenerative disorders, including PD and according to the recent researches chronic use of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) decreases the risk of PD in human. In the study the rat left Substantia Nigra Pars Compacta (SNc) have been destroyed using electrical lesion (1 mA; DC; 8 Sec) to induce PD model. Then aspirin (30, 60 mg kg(-1)) and celecoxib (4, 8 mg kg(-1)) have been administrated orally to parkinsonian rats. When the animals were suffered to PD Murprogo's Method evaluated the rigidity ofparkinsonian rats. Both selective COX-2 inhibitor (celecoxib) and non-selective COX-2 inhibitor (aspirin) decreased the rigidity of parkinsonian rats p<0.05 but rigidity recovery after administration the selective COX-2 inhibitor was more than non-selective COX-2 inhibitor. These findings are additional pharmacological information which has suggested the use of NSAIDs as alternative way to treat the rigidity of PD.
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PMID:Effects of aspirin and celecoxib on rigidity in a rat model of Parkinson's disease. 1909 Feb 41

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

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


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