Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P43026 (lipopolysaccharide)
 62,215 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammation is implicated in the progressive nature of neurodegenerative diseases, such as Parkinson's disease, but the mechanisms are poorly understood. A single systemic lipopolysaccharide (LPS, 5 mg/kg, i.p.) or tumor necrosis factor alpha (TNFalpha, 0.25 mg/kg, i.p.) injection was administered in adult wild-type mice and in mice lacking TNFalpha receptors (TNF R1/R2(-/-)) to discern the mechanisms of inflammation transfer from the periphery to the brain and the neurodegenerative consequences. Systemic LPS administration resulted in rapid brain TNFalpha increase that remained elevated for 10 months, while peripheral TNFalpha (serum and liver) had subsided by 9 h (serum) and 1 week (liver). Systemic TNFalpha and LPS administration activated microglia and increased expression of brain pro-inflammatory factors (i.e., TNFalpha, MCP-1, IL-1beta, and NF-kappaB p65) in wild-type mice, but not in TNF R1/R2(-/-) mice. Further, LPS reduced the number of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra (SN) by 23% at 7-months post-treatment, which progressed to 47% at 10 months. Together, these data demonstrate that through TNFalpha, peripheral inflammation in adult animals can: (1) activate brain microglia to produce chronically elevated pro-inflammatory factors; (2) induce delayed and progressive loss of DA neurons in the SN. These findings provide valuable insight into the potential pathogenesis and self-propelling nature of Parkinson's disease.
 ...
PMID:Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. 1720 72

Microglia play an important role in the inflammatory process that occurs in Parkinson's disease (PD). Activated microglia produce cytokines and neurotrophins and may have neurotoxic or neurotrophic effects. Because microglia are most proliferative and easily activated during the neonatal period, we examined the effects of neonatal microglia activated with lipopolysaccharide (LPS) on the nigro-striatal dopamine neurons in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), in comparison with activated microglia from the aged mice. By MPTP administration to neonatal mice, the number of dopamine neurons in the substantia nigra (SN) was decreased significantly, whereas that in the mice treated with LPS and MPTP was recovered to normal, along with significant microglial activation. Tyrosine hydroxylase (TH) activity, the levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and the levels of pro-inflammatory cytokines IL-1beta and IL-6 in the midbrain were elevated in the neonates treated with LPS and MPTP. On the contrary, although the number of dopamine neurons in the 60-week-old mice treated with MPTP was also decreased significantly, the microglial activation by LPS treatment caused a further decrease in their number. These results suggest that the activated microglia in neonatal mice are different from those in aged mice, with the former having neurotrophic potential toward the dopamine neurons in the SN, in contrast to the neurotoxic effect of the latter.
 ...
PMID:Activated microglia affect the nigro-striatal dopamine neurons differently in neonatal and aged mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 1746 35

Epidemiological studies have reported that smoking is associated with a lower incidence of Parkinson's disease (PD), leading to theories that smoking in general and nicotine in particular might be neuroprotective. Recent studies suggested cholinergic anti-inflammatory pathway-regulating microglial activation through alpha7 nicotinic receptors. In the present study, we used lipopolysaccharide (LPS)-induced in vitro and in vivo inflammation models to investigate whether nicotine has a protective effect on the dopaminergic system through an anti-inflammatory mechanism. Nicotine pretreatment considerably decreased microglial activation with significant reduction of tumour necrosis factor (TNF)-alpha mRNA expression and TNF-alpha release induced by LPS stimulation. In co-cultures of microglia and mesencephalic neurons, nicotine pretreatment significantly decreased the loss of tyrosine hydroxylase-immunopositive (TH-ip) cells, approximately twice more than the LPS-only treatment. alpha-Bungarotoxin, an alpha7 nicotinic acetylcholine receptor subunit-selective blocker, considerably blocked the inhibitory effects of nicotine on microglial activation and TH-ip neuronal loss. Chronic nicotine pretreatment in rats showed that TH-ip neuronal loss induced by LPS stimulation in the substantia nigra was dramatically decreased, which was clearly accompanied by a reduction in the formation of TNF-alpha. The present study demonstrated that nicotine has a neuroprotective effect on dopaminergic neurons via an anti-inflammatory mechanism mediated by the modulation of microglial activation. Along with various neuroprotective effects of nicotine, the anti-inflammatory mechanism of nicotine could have a major therapeutic implication in the preventive treatment of PD.
 ...
PMID:Neuroprotective effect of nicotine on dopaminergic neurons by anti-inflammatory action. 1758 Dec 57

Osteopontin (OPN) is a glycosylated phosphoprotein that regulates both oxidative stress and inflammatory processes. OPN is present in the rat substantia nigra (SN) and both protein and mRNA levels are up-regulated following a pro-inflammatory insult produced by lipopolysaccharide. We now report on the effects of lesioning the SN using 6-hydroxydopamine (6-OHDA) and mechanical vehicle-induced lesioning on OPN expression. Intranigral administration of 6-OHDA induced a marked time-dependent loss of tyrosine hydroxylase (TH) positive nigral cells. Vehicle administration also produced a loss of TH positive cells. This was small compared to 6-OHDA and due to mechanical damage during surgery. 6-OHDA and mechanical-induced cell loss was accompanied by an increase in OPN protein and mRNA expression. Both 6-OHDA and mechanical lesions resulted in equivalent time-dependent increases in OX-42 positive microglial cells. However, the elevation was far less marked following mechanical damage compared to 6-OHDA-induced cell death. 6-OHDA lesioning induced a slow up-regulation of GFAP positive astroglial cells but this was not present following mechanical damage. Importantly, both 6-OHDA and mechanical lesions resulted in an up-regulation in ED1 positive macrophages of equivalent magnitude and time course. There was co-localisation of OPN with ED1 positive cells but not TH, OX-42 or GFAP cells following both toxin and mechanical lesions. Nigral TH positive cell death of toxin or mechanical origin increases OPN expression in parallel with the up-regulation of ED1 positive macrophages. The increase in OPN/ED1 expression is independent of the extent of cell death. OPN appears to be an important regulator of nigral cell survival through its association with inflammatory events and its manipulation may provide a means of achieving neuroprotection in Parkinson's disease.
 ...
PMID:Osteopontin expression in activated glial cells following mechanical- or toxin-induced nigral dopaminergic cell loss. 1764 30

The potential neuroprotective action of the corticotrophin-releasing factor-related peptide urocortin (UCN) was investigated in the rat 6-hydroxydopamine (6-OHDA) and lipopolysaccharide (LPS) paradigms of Parkinson's disease. UCN (20 fmol) was either given at the same time as (T = 0) or 7 days after (T = +7) intracerebral 6-OHDA or LPS injection. At 14 days after 6-OHDA or LPS injection, circling behaviour was measured following apomorphine challenge. Circling was significantly lower in rats given UCN at either T = 0 or T = +7 compared with animals given 6-OHDA or LPS and vehicle. Sham-treated rats showed no circling. Consistent with these observations, striatal dopamine concentrations were markedly higher in 6-OHDA/LPS + UCN rats vs. 6-OHDA/LPS + vehicle groups. Additionally, L-dihydroxyphenylalanine production by tyrosine hydroxylase was greatly reduced in the striata of 6-OHDA/LPS + vehicle rats, whereas this was not the case in rats coadministered UCN. Finally, the numbers of tyrosine hydroxylase-positive cells recorded in the substantia nigra of 6-OHDA/LPS + vehicle-treated animals were markedly lower than those of sham-operated or 6-OHDA/LPS + UCN rats. Critically, UCN was effective in reversing lesion-induced deficits when given either at the same time as or 7 days after the neurotoxic insult. To our knowledge, this is the first time that such an effect has been demonstrated in vivo. The apparent ability of UCN to arrest the progression of or even reverse nigral lesions once established suggests that pharmacological manipulation of this system could have substantial therapeutic utility.
 ...
PMID:The corticotrophin-releasing factor-like peptide urocortin reverses key deficits in two rodent models of Parkinson's disease. 1765 Jan 14

A cDNA clone encoding tyrosine hydroxylase (TH) was isolated from larval fat body of immunized Samia cynthia ricini. In naive larvae, the TH gene was expressed only in the brain, but strongly induced in fat body and hemocytes after injecting UV-killed bacteria. The induction of the gene was rather short-lived compared to that of antibacterial protein genes, reaching the maximum levels 6h after bacterial challenge, and then quickly diminished. A strong induction of the gene expression was caused by both Gram-negative and positive bacteria and zymosan, but little if any by soluble peptidoglycan or lipopolysaccharide. A possible role of TH in the fat body of bacteria-challenged larvae would be to supply catecholamines as the substrate for phenoloxidase leading to melanization, working together with dopa decarboxylase.
 ...
PMID:Induction of tyrosine hydroxylase gene expression by bacteria in the fat body of eri-silkworm, Samia cynthia ricini. 1817 96

Although white matter damage is a fundamental neuropathological feature of periventricular leukomalacia (PVL), the motor and cognitive deficits observed later in infants with PVL indicate the possible involvement of cerebral neuronal dysfunction. Using a previously developed rat model of white matter injury induced by cerebral lipopolysaccharide (LPS) injection, we investigated whether LPS exposure also results in neuronal injury in the neonatal brain and whether alpha-phenyl-n-tert-butyl-nitrone (PBN), an antioxidant, offers protection against LPS-induced neuronal injury. A stereotactic intracerebral injection of LPS (1 mg/kg) was performed in Sprague-Dawley rats (postnatal day 5) and control rats were injected with sterile saline. LPS exposure resulted in axonal and neuronal injury in the cerebral cortex as indicated by elevated expression of beta-amyloid precursor protein, altered axonal length and width, and increased size of cortical neuronal nuclei. LPS exposure also caused loss of tyrosine hydroxylase positive neurons in the substantia nigra and the ventral tegmental areas of the rat brain. Treatments with PBN (100 mg/kg) significantly reduced LPS-induced neuronal and axonal damage. The protection of PBN was associated with an attenuation of oxidative stress induced by LPS as indicated by the reduced number of 4-hydroxynonenal, malondialdehyde or nitrotyrosine positive cells in the cortical area following LPS exposure, and with the reduction in microglial activation stimulated by LPS. The finding that an inflammatory environment may cause both white matter and neuronal injury in the neonatal brain supports the possible anatomical correlate for the intellectual deficits and the other cortical and deep gray neuronal dysfunctions associated with PVL. The protection of PBN may indicate the potential usefulness of antioxidants for treatment of these neuronal dysfunctions.
 ...
PMID:Alpha-Phenyl-n-tert-butyl-nitrone attenuates lipopolysaccharide-induced neuronal injury in the neonatal rat brain. 1819 5

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by a selective loss of dopaminergic neurons in the substantia nigra (SN). It has been suggested that microglial inflammation augments the progression of PD. Neuromelanin (NM), a complex polymer pigment found in catecholaminergic neurons, has sparked interest because of the suggestion that NM is involved in cell death in Parkinson's disease, possibly via microglia activation. To further investigate the possible role of NM in the pathogenesis of PD, we conducted in vivo experiments to find out whether microglial cells become activated after injection of human neuromelanin (NM) into (1) the cerebral cortex or (2) the substantia nigra to monitor in this PD-relevant model both microglial activation and possible neurodegeneration. In this study, adult male Wistar rats received an intracerebral injection of either NM, bacterial lipopolysaccharide (LPS, positive control), phosphate-buffered saline (PBS, negative control) or colloidal gold suspension (negative particular control). After different survival times (1, 8 or 12 weeks), brain slices from the cerebral cortex or substantia nigra (SN, 1 week) were stained with Iba-1 and/or GFAP antibody to monitor microglial and astrocytic reaction, and with tyrosine hydroxylase (TH) to monitor dopaminergic cell survival (SN group only). The injection of LPS induced a strong inflammatory response in the cortex as well in the substantia nigra. Similar results could be obtained after NM injection, while the injection of PBS or gold suspension showed only moderate or no glial activation. However, the inflammatory response declined during the time course. In the SN group, there was, apart from strong microglia activation, a significant dopaminergic cell loss after 1 week of survival time. Our findings clearly indicate that extracellular NM could be one of the key molecules leading to microglial activation and neuronal cell death in the substantia nigra. This may be highly relevant to the elucidation of therapeutic strategies in PD.
 ...
PMID:Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. 1834 32

Neonatal exposure to infectious agents may result in long-term neurological disability, and is particularly associated with the subsequent development of motor and cognitive disturbances. Our previous studies have shown that treatment with alpha-phenyl-n-tert-butyl-nitrone (PBN) following exposure to lipopolysaccharide (LPS) reduces LPS-induced brain injury in the neonatal rat. To examine whether PBN has long-lasting protective effects and ameliorates LPS-induced motor and cognitive dysfunction, PBN (100 mg/kg) was administered intraperitoneally 5 min after an LPS (1 mg/kg) intracerebral injection in postnatal day 5 (P5) Sprague-Dawley rat pups. Neurobehavioral tests were carried out from P3 to P21, and brain injury was examined at 24 h and 16 days after LPS injection. Neonatal LPS exposure resulted in hyperactivity from P13 to P17 in the open field task as compared with the control rat. Neurobehavioral deficits that were still observable at P21 included dysfunction in the beam-walking and pole tests, learning and memory deficits in the passive avoidance task, and less anxiety-like response in the elevated plus-maze task. These behavioral findings were matched by LPS-induced axonal injury in the CA1 region of the middle dorsal hippocampus (HP), reduction in the size of the HP and the number of neurons in the CA1 region of the middle dorsal HP, and loss of tyrosine hydroxylase immunoreactivity in neurons in the substantia nigra and ventral tegmental areas. Treatment with PBN provided long-lasting protection against the LPS-induced axonal injury and neuronal loss, and improved the associated neurological dysfunctions in juvenile rats.
 ...
PMID:Alpha-phenyl-n-tert-butyl-nitrone ameliorates hippocampal injury and improves learning and memory in juvenile rats following neonatal exposure to lipopolysaccharide. 1836 24

The D2/D3 dopamine receptor agonist pramipexole, protects against toxin-induced dopaminergic neuronal destruction but its mechanism of action is unknown. Inflammation following glial cell activation contributes to cell death in Parkinson's disease and we now report on the effects of acute or chronic administration of pramipexole on lipopolysaccharide (LPS) induced inflammation and nigral dopaminergic cell death in the rat. At 48 h and 30 days following supranigral administration of LPS, approximately 70% of tyrosine hydroxylase (TH) immunoreactive (-ir) cells in substantia nigra had degenerated with a corresponding loss of TH-ir terminals in the striatum. In rats acutely treated with pramipexole (2x1 mg/kg; s.c.) 48 h following LPS application, there was no difference in the number of TH-ir cells or terminals compared to LPS-treated rats receiving vehicle. However, the continuous subcutaneous infusion of pramipexole for 7 days prior to LPS and 21 days subsequently, produced a marked preservation of both TH-ir cells and terminals. At 48 h or 30 days, LPS induced an up-regulation of ubiquitin-ir within the nigral TH-ir neurones, which was reduced by pramipexole treatment. Thirty days following supranigral LPS administration (9 days after the end of infusion), (+)-amphetamine (5 mg/kg, i.p.) caused robust ipsiversive rotation. In rats treated with LPS but receiving continuous subcutaneous administration of pramipexole, (+)-amphetamine-induced rotation was markedly reduced. LPS-induced increase in the levels of inflammatory markers, were not affected by either acute administration or continuous infusion of pramipexole. Continuous infusion of pramipexole protected dopaminergic neurones against inflammation induced degeneration but without modification of the inflammatory response.
 ...
PMID:Continuous subcutaneous infusion of pramipexole protects against lipopolysaccharide-induced dopaminergic cell death without affecting the inflammatory response. 1857 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>