UNIPROT:P43026 - FACTA Search

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Query: UNIPROT:P43026 (lipopolysaccharide)
62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation participates in the pathogenesis and progression of Parkinson's disease, in which microglia play a key role. Inhibition of microglia activation has been shown to attenuate inflammation-mediated dopaminergic neurodegeneration. In this study, we found that genistein, the primary soybean isoflavone, concentration-dependently attenuated the lipopolysaccharide-induced decrease in dopamine uptake and loss of tyrosine hydroxylase-immunoreactive neurons in rat mesencephalic neuron-glia cultures. Genistein also inhibited lipopolysaccharide-induced microglia activation and production of tumor necrosis factor-alpha, nitric oxide and superoxide in mesencephalic neuron-glia cultures and microglia-enriched cultures. Our results indicate that genistein may protect dopaminergic neurons from lipopolysaccharide-induced injury and its effective inhibition of microglia activation may be one of the mechanisms.
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PMID:Genistein protects dopaminergic neurons by inhibiting microglial activation. 1570 33

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

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

The present study was undertaken to explore involvement of nitric oxide (NO) in the experimental models of Parkinson's disease. Neurodegeneration was induced by unilateral injections of 6-hydroxydopamine (6-OHDA) or lipopolysaccharide (LPS) in the right striatum. Lesions were functionally evaluated by amphetamine-induced asymmetrical behaviour and by decrease in the tyrosine hydroxylase (TH) immunostaining. An induction in the expression of iNOS and augmentation in nitrite content was observed in both the models. The extent of increase in iNOS expression was, however, different but the elevation in the nitrite content was comparable in both the models. The increase in iNOS expression inversely correlated with the tyrosine hydroxylase (TH) immunolabeling. Animals pretreated with a NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME), exhibited complete protection against amphetamine induced rotations in both the models. Thus, augmented NO availability subsequent to iNOS induction seems to play an important role in the initial phase of neurodegeneration.
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PMID:Involvement of nitric oxide in neurodegeneration: a study on the experimental models of Parkinson's disease. 1594 31

Sustained reactive microgliosis may contribute to the progressive degeneration of nigral dopaminergic neurons in Parkinson's disease (PD), in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposed human and in non-human primates. However, the temporal relationship between glial cell activation and nigral cell death is relatively unexplored. Consequently, the effects of acute (24 h) and chronic (30 days) glial cell activation induced by unilateral supranigral lipopolysaccharide (LPS) administration were studied in rats. At 24 h, LPS administration caused a marked reduction in the number of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the substantia nigra (SN) but striatal TH-ir was unaffected. By 30 days, the loss of TH-positive neurons in the LPS-treated nigra was no greater than at 24 h although a heterogeneous loss of striatal TH-ir was present. The loss of nigrostriatal neurons was of functional significance, as at 30 days, LPS-treated rats exhibited ipsiversive circling in response to (+)-amphetamine administration. At 24 h, there was a moderate increase in glial fibrillary acidic protein (GFAP)-ir astrocytes in the SN but a marked elevation of p47phox positive OX-42-ir microglia, and intense inducible nitric oxide synthase (iNOS)-ir and 3-nitrotyrosine (3-NT)-ir was present. However, by 30 days the morphology of OX-42-ir microglia returned to a resting state, the numbers were greatly reduced and no 3-NT-ir was present. At 30 days, GFAP-ir astrocytes were markedly increased in number and iNOS-ir was present in fibrillar astrocyte-like cells. This study shows that acute glial activation leading to dopaminergic neuron degeneration is an acute short-lasting response that does not itself perpetuate cell death or lead to prolonged microglial activation.
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PMID:The acute and the long-term effects of nigral lipopolysaccharide administration on dopaminergic dysfunction and glial cell activation. 1604 85

Preferential brain white matter injury and hypomyelination induced by intracerebral administration of the endotoxin lipopolysaccharide (LPS) in the neonatal rat brain has been characterized as associated with the activation of microglia. To examine whether inhibition of microglial activation might provide protection against LPS-induced brain injury and behavioral deficits, minocycline (45 mg/kg) was administered intraperitoneally 12 hr before and immediately after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rats and then every 24 hr for 3 days. Brain injury and myelination were examined on postnatal day 21 and the tests for neurobehavioral toxicity were carried out from P3 to P21. LPS administration resulted in severe white matter injury, enlarged ventricles, deficits in the hippocampus, loss of oligodendrocytes and tyrosine hydroxylase neurons, damage to axons and dendrites, and impaired myelination as indicated by the decrease in myelin basic protein immunostaining in the P21 rat brain. LPS administration also significantly affected physical development (body weight) and neurobehavioral performance, such as righting reflex, wire hanging maneuver, cliff avoidance, locomotor activity, gait analysis, and responses in the elevated plus-maze and passive avoidance task. Treatment with minocycline significantly attenuated the LPS-induced brain injury and improved neurobehavioral performance. The protective effect of minocycline was associated with its ability to attenuate LPS-induced microglial activation. These results suggest that inhibition of microglial activation by minocycline may have long-term protective effects in the neonatal brain on infection-induced brain injury and associated neurologic dysfunction in the rat.
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PMID:Minocycline reduces lipopolysaccharide-induced neurological dysfunction and brain injury in the neonatal rat. 1611 91

Increasing evidence suggests that abnormal iron handling may be involved in the pathogenesis of Parkinson's disease. The present study investigates the role of iron and the iron-storage protein ferritin in inflammation-induced degeneration of dopaminergic neurons of the substantia nigra pars compacta. Injection of lipopolysaccharide into the globus pallidus of young and middle-aged rats substantially decreased tyrosine hydroxylase immunostaining in substantia nigra pars compacta four weeks after injection. Loss of tyrosine hydroxylase expression was accompanied by increased iron and ferritin levels in glial cells of the substantia nigra pars reticulata. Despite greater increases in nigral iron levels, ferritin induction was less pronounced in older rats, suggesting the regulation of ferritin was compromised with age. Automated movement tracking analyses showed that young rats recovered from LPS-induced locomotor deficits within four weeks, yet older rats failed to improve on measures of speed and total distance moved. Intrapallidal lipopolysaccharide injection also increased expression of alpha-synuclein and ubiquitin in tyrosine hydroxylase-positive neurons of the substantia nigra pars compacta. These results suggest that pallidal inflammation significantly increases stress on dopamine-containing neurons in the substantia nigra pars compacta. Alterations in nigral iron levels and protein handing may increase the vulnerability of nigral neurons to degenerative processes.
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PMID:Intrapallidal lipopolysaccharide injection increases iron and ferritin levels in glia of the rat substantia nigra and induces locomotor deficits. 1616 92

Here, we report that leucine enkephalin (LE) is neuroprotective to dopaminergic (DA) neurons at femtomolar concentrations through anti-inflammatory properties. Mesencephalic neuron-glia cultures pretreated with femtomolar concentrations of LE (10(-15)-10(-13) M) protected DA neurons from lipopolysaccharide (LPS)-induced DA neurotoxicity, as determined by DA uptake assay and tyrosine hydroxylase (TH) immunocytochemistry (ICC). However, des-tyrosine leucine enkephalin (DTLE), an LE analogue that is missing the tyrosine residue required for binding to the kappa opioid receptor, was also neuroprotective (10(-15)-10(-13) M), as determined by DA uptake assay and TH ICC. Both LE and DTLE (10(-15)-10(-13) M) reduced LPS-induced superoxide production from microglia-enriched cultures. Further, both LE and DTLE (10(-14), 10(-13) M) reduced the LPS-induced tumor necrosis factor-alpha (TNFalpha) mRNA and TNFalpha protein from PHOX+/+ microglia, as determined by quantitative real-time RT-PCR and ELISA analysis in mesencephalic neuron-glia cultures, respectively. However, both peptides failed to inhibit TNFalpha expression in PHOX-/- cultures, which are unable to produce extracellular superoxide in response to LPS. Additionally, LE and DTLE (10(-14), 10(-13) M) failed to show any neuroprotection against LPS in PHOX-/- cultures. Together, these data indicate that LE and DTLE are neuroprotective at femtomolar concentrations through the inhibition of oxidative insult associated with microglial NADPH oxidase and the attenuation of the ROS-mediated amplification of TNFalpha gene expression in microglia.
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PMID:Microglial NADPH oxidase mediates leucine enkephalin dopaminergic neuroprotection. 1617 14

Accumulating evidences suggest that neuroinflammation is involved in the progressive death of dopaminergic neurons in Parkinson's disease. Several studies have shown that intranigral injection of lipopolysaccharide induces inflammation in the substantia nigra leading to death of tyrosine hydroxylase-positive cells. To better understand how the inflammatory response gives rise to neurotoxicity we induced inflammation in substantia nigra by injecting lipopolysaccharide. The damage of substantia nigra dopaminergic neurons was evaluated by immunohistochemistry, reverse transcription-PCR and Western blot analysis of tyrosine hydroxylase. In parallel, activation of microglial cells, a hallmark of inflammation in CNS, was revealed by immunohistochemistry. Similarly the expression of molecules involved in the inflammatory response and apoptotic pathway was also tested, such as cytokines (tumor necrosis factor-alpha, interleukin-1beta, interleukin-6), inducible nitric oxide synthase and caspase-11. Tyrosine hydroxylase expression (both mRNA and protein) started to decrease around 3 days post-injection. At the mRNA level, our results showed that the cytokines expression peaked shortly (3-6 h) after lipopolysaccharide injection, followed by the induction of inducible nitric oxide synthase and caspase-11 (14 h). However, inducible nitric oxide synthase protein peaked at 24 h and lasted for 14 days. The lipopolysaccharide-induced loss of substantia nigra dopaminergic neurons was partially inhibited by co-injection of lipopolysaccharide with S-methylisothiourea, an inducible nitric oxide synthase inhibitor. Co-injections of lipopolysaccharide with SB203580, a p38 MAP kinase inhibitor, reduced inducible nitric oxide synthase and caspase-11 mRNA expression, and also rescued dopaminergic neurons in substantia nigra. In summary, this is the first report to describe in vivo the temporal profile of the expression of these inflammatory mediators and proteins involved in dopaminergic neuronal death after intranigral injection of lipopolysaccharide. Moreover data strongly support that lipopolysaccharide-induced dopaminergic cellular death in substantia nigra could be mediated, at least in part, by the p38 signal pathway leading to activation of inducible nitric oxide synthase and caspase-11.
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PMID:Role of p38 and inducible nitric oxide synthase in the in vivo dopaminergic cells' degeneration induced by inflammatory processes after lipopolysaccharide injection. 1671 9

Microglial activation is implicated in the progressive nature of numerous neurodegenerative diseases, including Parkinson's disease. Using primary rat mesencephalic neuron-glia cultures, we found that pituitary adenylate cyclase-activating polypeptide (PACAP) 38, PACAP27, and its internal peptide, Gly-Ile-Phe (GIF; PACAP4-6), are neuroprotective at 10(-13) M against lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity, as determined by [(3)H]DA uptake and the number of tyrosine hydroxylase-immunoreactive neurons. PACAP38 and GIF also protected against 1-methyl-4-phenylpyridinium(+)-induced neurotoxicity but only in cultures containing microglia. PACAP38 and GIF ameliorated the production of microglia-derived reactive oxygen species (ROS), where both LPS- and phorbol 12-myristate 13-acetate-induced superoxide and intracellular ROS were inhibited. The critical role of NADPH oxidase for GIF and PACAP38 neuroprotection against LPS-induced DA neurotoxicity was demonstrated using neuron-glia cultures from mice deficient in NADPH oxidase (PHOX(-/-)), where PACAP38 and GIF reduced tumor necrosis factor alpha production and were neuroprotective only in PHOX(+/+) cultures and not in PHOX(-/-) cultures. Pretreatment with PACAP6-38 (3 microM; PACAP-specific receptor antagonist) was unable to attenuate PACAP38, PACAP27, or GIF (10(-13) M) neuroprotection. PACAP38 and GIF (10(-13) M) failed to induce cAMP in neuronglia cultures, supporting that the neuroprotective effect was independent of traditional high-affinity PACAP receptors. Pharmacophore analysis revealed that GIF shares common chemical properties (hydrogen bond acceptor, positive ionizable, and hydrophobic regions) with other subpicomolar-acting compounds known to inhibit NADPH oxidase: naloxone, dextromethorphan, and Gly-Gly-Phe. These results indicate a common high-affinity site of action across numerous diverse peptides and compounds, revealing a basic neuropeptide regulatory mechanism that inhibits microglia-derived oxidative stress and promotes neuron survival.
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PMID:Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and PACAP4-6 are neuroprotective through inhibition of NADPH oxidase: potent regulators of microglia-mediated oxidative stress. 1689 16

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