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)

Converging lines of evidence suggest that neuroinflammatory processes may account for the progressive death of dopaminergic neurons in Parkinson's disease (PD). Therefore, anti-inflammatory strategies have attracted much interest for their potential to prevent further deterioration of PD. Our previous study showed that triptolide, a traditional Chinese herbal compound with anti-inflammatory and immunosuppressive properties, protected dopaminergic neurons from lipopolysaccharide (LPS)-induced damage in primary embryonic midbrain cell cultures. To examine further if triptolide can protect dopaminergic neurons from inflammation-mediated damage in vivo, microglial activation and injury of dopaminergic neurons were induced by LPS intranigral injection, and the effects of triptolide treatment on microglial activation and survival ratio and function of dopaminergic neurons were investigated. Our results demonstrated that microglial activation induced by a single intranigral dose of 10 mug of LPS reduced the survival ratio of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) to 29% and the content of dopamine (DA) in striatum to 37% of the non-injected side. Intriguingly, treatment with triptolide of 5 mug/kg for 24 days once per day dramatically improved the survival rate of TH-ir neurons in the SNpc to 79% of the non-injected side. Meanwhile, treatment with triptolide of 1 or 5 mug/kg for 24 days once per day significantly improved DA level in striatum to 70% and 68% of the non-injected side, respectively. Complement receptor 3 (CR3) immunohistochemical staining revealed that triptolide treatment potently inhibited LPS-elicited deleterious activation of microglia in SNpc. The excessive production of cytokines, such as tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta, was significantly abolished by triptolide administration. These results, together with our previous data in vitro, highly suggest the effectiveness of triptolide in protecting dopaminergic neurons against inflammatory challenge.
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PMID:Triptolide protects dopaminergic neurons from inflammation-mediated damage induced by lipopolysaccharide intranigral injection. 1575 70

Parkinson's disease is a neurological disorder involving the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. There is increasing evidence that inflammation plays a role in the propagation of neurodegenerative processes in Parkinson's disease. We investigated the neuroprotective effects of simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A inhibitor with anti-inflammatory properties, in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Oral administration of simvastatin attenuated the depletion of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid in the striatum caused by MPTP in a dose-dependent manner. Simvastatin also inhibited the formation of 3-nitrotyrosine in striatal proteins in MPTP-treated mice. Simvastatin had no effect on cholesterol concentrations in the plasma or in the striatum. Simvastatin inhibited the production of tumor necrosis factor (TNF)-alpha, nitric oxide, and superoxide in cultured rat microglia stimulated by lipopolysaccharide. The results suggest that simvastatin inhibits the formation of TNF-alpha and peroxynitrite in activated microglia thereby protecting dopaminergic neurons from inflammatory damage. Simvastatin may be a potential new treatment to slow the progression of Parkinson's disease.
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PMID:Simvastatin prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced striatal dopamine depletion and protein tyrosine nitration in mice. 1577 46

Parkinson's disease is a neurodegenerative disorder characterized by progressive degeneration of dopaminergic (DA) neurons in the substantia nigra. Accumulating evidence supports the notion that neuroinflammation is involved in the pathogenesis of this disease. Valproate (VPA) has long been used for the treatment of seizures and bipolar mood disorder. In vivo and in vitro studies have demonstrated that VPA has neuroprotective and neurotrophic actions. In this study, using primary neuron-glia cultures from rat midbrain, we demonstrated that VPA is a potent neuroprotective agent against lipopolysaccharide (LPS)-induced neurotoxicity. Results showed that pretreatment with 0.6 mM VPA for 48 h robustly attenuated LPS-induced degeneration of dopaminergic neurons as determined by [(3)H] dopamine uptake and counting of the number of TH-ir neurons. The neuroprotective effect of VPA was concentration-dependent and was mediated, at least in part, through a decrease in levels of pro-inflammatory factors released from activated microglia. Specifically, LPS-induced increase in the release of TNFa, NO, and intracellular reactive oxygen species was markedly reduced in cultures pretreated with VPA. These anti-inflammatory effects of VPA were time and concentration-dependent correlated with a decrease in the number of microglia. Thus, our results demonstrate that protracted VPA pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity through a reduction in levels of released pro-inflammatory factors, and further suggest that these anti-inflammatory effects may be contributed by VPA-induced reduction of microglia cell number. Taken together, our study reinforces the view that VPA may have utility in treating Parkinson's disease.
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PMID:Valproate pretreatment protects dopaminergic neurons from LPS-induced neurotoxicity in rat primary midbrain cultures: role of microglia. 1579 May 40

Inflammation in the brain has increasingly been recognized to play an important role in the pathogenesis of several neurodegenerative disorders, including Parkinson's disease (PD). Progress in the search for effective therapeutic strategies that can halt this degenerative process remains limited. We previously showed that micromolar concentrations of dextromethorphan (DM), a major ingredient of widely used antitussive remedies, reduced the inflammation-mediated degeneration of dopaminergic neurons through the inhibition of microglial activation. In this study, we report that femto- and micromolar concentrations of DM (both pre- and post-treatment) showed equal efficacy in protecting lipopolysaccharide (LPS) -induced dopaminergic neuron death in midbrain neuron-glia cultures. Both concentrations of DM decreased LPS-induced release of nitric oxide, tumor necrosis factor-alpha, prostaglandin E2 and superoxide from microglia in comparable degrees. The important role of superoxide was demonstrated by DM's failure to show a neuroprotective effect in neuron-glia cultures from NADPH oxidase-deficient mice. These results suggest that the neuroprotective effect elicited by femtomolar concentrations of DM is mediated through the inhibition of LPS-induced proinflammatory factors, especially superoxide. These findings suggest a novel therapeutic concept of using "ultra-low" drug concentrations for the intervention of inflammation-related neurodegenerative diseases.
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PMID:Femtomolar concentrations of dextromethorphan protect mesencephalic dopaminergic neurons from inflammatory damage. 1579 Sep 98

Microglial activation and inflammation are associated with progressive neuronal apoptosis in neurodegenerative human brain disorders. We sought to investigate molecular signaling mechanisms that govern activation of microglia in apoptotic neuronal degeneration. We report here that the active form of matrix metalloproteinase-3 (MMP-3) was released into the serum-deprived media (SDM) of PC12 cells and other media of apoptotic neuronal cells within 2-6 h of treatment of the cells, and SDM and catalytic domain of recombinant MMP-3 (cMMP-3) activated microglia in primary microglia cultures as well as BV2 cells, a mouse microglia cell line. Both SDM and cMMP-3 induced generation of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), IL-1beta, and interleukin-1 receptor antagonist but not IL-12 and inducible nitric oxide synthase, which are readily induced by lipopolysaccharide, in microglia, suggesting that there is a characteristic pattern of microglial cytokine induction by apoptotic neurons. Neither glial cell line-derived neurotrophic factor nor anti-inflammatory cytokines, such as IL-10 and transforming growth factor-beta1, were induced. SDM and cMMP-3 extensively released TNF-alpha from microglia and activated the nuclear factor-kappaB pathway, and these microglial responses were totally abolished by preincubation with an MMP-3 inhibitor, NNGH [N-isobutyl-N-(4-methoxyphenylsulfonyl)-glycylhydroxamic acid]. MMP-3-mediated microglial activation mostly depended on ERK (extracellular signal-regulated kinase) phosphorylation but not much on either JNK (c-Jun N-terminal protein kinase) or p38 activation. Conditioned medium of SDM- or cMMP-3-activated BV2 cells caused apoptosis of PC12 cells. These results strongly suggest that the distinctive signal of neuronal apoptosis is the release of active form of MMP-3 that activates microglia and subsequently exacerbates neuronal degeneration. Therefore, the release of MMP-3 from apoptotic neurons may play a major role in degenerative human brain disorders, such as Parkinson's disease.
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PMID:Matrix metalloproteinase-3: a novel signaling proteinase from apoptotic neuronal cells that activates microglia. 1581 1

In most neurodegenerative disorders, including multiple sclerosis, Parkinson disease, and Alzheimer disease, a massive neuronal cell death occurs as a consequence of an uncontrolled inflammatory response, where activated astrocytes and microglia and their cytotoxic agents play a crucial pathological role. Current treatments for these diseases are not effective. In the present study we investigate the effect of thiadiazolidinone derivatives, which have been recently suggested to play a role in neurodegenerative disorders. We have found that thiadiazolidinones are potent neuroprotector compounds. Thiadiazolidinones inhibited inflammatory activation of cultured brain astrocytes and microglia by diminishing lipopolysaccharide-induced interleukin 6, tumor necrosis factor alpha, inducible nitric-oxide synthase, and inducible cyclooxygenase type 2 expression. In addition, thiadiazolidinones inhibited tumor necrosis factor-alpha and nitric oxide production and, concomitantly, protected cortical neurons from cell death induced by the cell-free supernatant from activated microglia. The neuroprotective effects of thiadiazolidinones are completely inhibited by the peroxisome proliferator-activated receptor gamma antagonist GW9662. In contrast the glycogen synthase kinase 3beta inhibitor LiCl did not show any effect. These findings suggest that thiadiazolidinones potently attenuate lipopolysaccharide-induced neuroinflammation and reduces neuronal death by a mechanism dependent of peroxisome proliferator-activated receptor gamma activation.
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PMID:Regulation of inflammatory response in neural cells in vitro by thiadiazolidinones derivatives through peroxisome proliferator-activated receptor gamma activation. 1581 69

Nigral cell death in Parkinson's disease is characterized by glial cell activation leading to inflammatory changes. Osteopontin (OPN) is a glycosylated phosphoprotein that is induced by inflammatory mediators and which we have previously shown to be present in the substantia nigra. However, the role of OPN in the nigral inflammation is not known. We now report on the effects of lipopolysaccharide (LPS)-induced glial cell activation in the substantia nigra of rats on OPN expression. LPS administration induced dopaminergic cell death as shown by reduced nigral tyrosine hydroxylase immunoreactivity. There was a corresponding time-dependent increase in both OPN mRNA, which was maximal at 48 h, and protein levels, which peaked at 72 h before returning to control levels by 120 h. This increase was accompanied by marked reactive gliosis as shown by increased OX-42, glial fibrillary acidic protein (GFAP) and ED1 immunoreactivity. OX-42-positive cells increased in a time-dependent manner, peaking at 72 h before returning to control levels at 120 h. Similarly, ED1-positive cells were present in their greatest numbers at 24 h but then gradually declined. These changes mirrored the alterations occurring in OPN protein and OPN mRNA, respectively. In contrast, GFAP-positive cells only started to increase in number at 120 h. Colocalization studies showed that OPN was present in both ED1- and OX-42-positive cells but not in GFAP-positive cells. These data confirm that intranigral injection of LPS induces a rapid and marked gliosis that accompanies the loss of tyrosine hydroxylase-positive neurones and suggest that, after glial cell activation, enhanced expression of OPN occurs linked to increased numbers of microglia and/or macrophages. This suggests that OPN may be functionally important in the control of inflammatory changes.
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PMID:Increased osteopontin expression following intranigral lipopolysaccharide injection in the rat. 1586 84

Parkinson's disease is characterized by the progressive degeneration of midbrain dopaminergic neurons. Several studies have examined the effects of the dopaminergic neurotrophins growth/differentiation factor 5 (GDF5) and glial cell line-derived neurotrophic factor (GDNF) on these neurons in vitro. However, there is little information regarding their effects on astroglial cells. Here, the effects of GDF5 and GDNF on dopaminergic neuronal and astroglial survival and differentiation in embryonic rat midbrain cultures were examined. Both GDF5 and GDNF enhanced the survival and differentiation of dopaminergic neurons. GDF5 significantly increased the survival of astroglial cells, whereas GDNF had no significant effect on these cells. The possible involvement of astroglia in the dopaminergic neurotrophic effect induced by GDF5 was investigated by examining the effect of GDF5 on the survival of dopaminergic neurons in glia-depleted midbrain cultures. There was no significant difference between the survival of dopaminergic neurons in glia-depleted cultures treated with GDF5 and that in mixed cell cultures treated with GDF5, suggesting that GDF5 acts directly on dopaminergic neurons in exerting its neurotrophic effect. GDF5 and GDNF have been established as potent neurotrophic factors for dopaminergic neurons. However, the effects of adding a combination of these neurotrophins to midbrain cultures have not been previously examined. The present study found that combined treatment with GDF5 and GDNF significantly increased the survival of dopaminergic neurons in cultures compared with that in cultures treated with either neurotrophin alone. This was an additive effect, indicating that these neurotrophins act on separate subpopulations of dopaminergic neurons.
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PMID:Differential effects of growth/differentiation factor 5 and glial cell line-derived neurotrophic factor on dopaminergic neurons and astroglia in cultures of embryonic rat midbrain. 1588 Jul 84

In Parkinson's disease (PD), post-mortem examination reveals a loss of dopaminergic (DA) neurons in the substantia nigra (SN) associated with a massive astrogliosis and the presence of activated microglial cells. Similarly, microglial activation has also been reported to be associated with the loss of DA neurons in animal models of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, annonacine and lipopolysaccharide (LPS). Recent evidence suggests that the disease may progress even when the initial cause of neuronal degeneration has disappeared, raising the possibility that toxic substances released by glial cells could be involved in the propagation of neuronal degeneration. Inhibition of the glial reaction and the inflammatory processes may thus represent a therapeutic target to reduce neuronal degeneration in PD.
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PMID:Neuroinflammatory processes in Parkinson's disease. 1588 30

Growth/differentiation factor 5 (GDF5) is a member of the transforming growth factor-beta superfamily that is expressed in the developing CNS, including the ventral mesencephalon (VM). GDF5 has been shown to increase the survival of dopaminergic neurones in animal models of Parkinson's disease. This study was aimed at characterising the effects of GDF5 on dopaminergic neurones in vitro. Treatment with GDF5 induced a three-fold increase in the number of dopaminergic neurones in embryonic day 14 rat VM cultures after six days in vitro. A significant increase was also observed in the numbers of astrocytes in GDF5-treated cultures. GDF5 treatment also had significant effects on the morphology of dopaminergic neurones in these cultures; total neurite length, number of branch points and somal area were all significantly increased after six days in vitro. Analysis of neurite length and numbers of branch points at each level of the neuritic field revealed that the most pronounced effects of GDF5 were on the secondary and tertiary levels of the neuritic field. The specific type I receptor for GDF5, bone morphogenetic protein receptor (BMPR)-Ib, was found to be strongly expressed in freshly-dissected E14 VM tissue, but its expression was lost with increasing time in culture. Accordingly, treatment with GDF5 for 24 h from the time of plating induced increases in the numbers of dopaminergic neurones, while treatment with GDF5 for 24 h after six days in vitro did not. This study shows that GDF5 can promote both the survival and morphological differentiation of VM dopaminergic neurones in vitro, lending support to its potential as a candidate dopaminergic neurotrophin for use in the treatment of Parkinson's disease.
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PMID:Effects of growth/differentiation factor 5 on the survival and morphology of embryonic rat midbrain dopaminergic neurones in vitro. 1590 56


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