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)

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

The present study investigated the effects on general activity, COX-2 and TH protein expression of intranigral neurotoxins LPS, MPTP or 6-OHDA infusion in rats. Results indicate that LPS produced an increase in locomotion frequency (3 and 7 days after surgery) and a strong up-regulation of COX-2 protein 16 and 24 h after surgery, as observed in the substantia nigra (SN). The MPTP model generated impairment in locomotion frequency 24 h after surgery. Besides, MPTP caused a marked up-regulation in COX-2 protein observed in the SN 16 h after surgery. Moreover, the 6-OHDA model produced severe motor impairment indicated by the decrease in locomotion (24 h) and rearing (24 h, 3 and 7 days) frequencies and also an increase in latency (24 h, 3 and 7 days) and immobility (24 h and 3 days) times. We also demonstrated an up-regulation of COX-2, which occurred in the SN 4-24 h after surgery. TH protein did not appear to be reduced in the striatum in the groups lesioned with the neurotoxins. In contrast, the TH content of SN was significantly reduced in the groups lesioned with the very same neurotoxins. For all the models analyzed, we observed no statistical differences in the expression of COX-2 in the striatum along the time-points. The results of the present study suggest that COX-2 induction patterns differ in function of the neurotoxin tested. Such time-dependent induction has been found to be relatively constant, a fact of great significance considering the importance of the neuroinflammatory process in Parkinson's disease.
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PMID:Different parkinsonism models produce a time-dependent induction of COX-2 in the substantia nigra of rats. 1678 89

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.
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PMID:Systemic LPS causes chronic neuroinflammation and progressive neurodegeneration. 1720 72

Parkinson's Disease (PD) is a degenerative neurological disorder that typically manifests symptoms in late adulthood, after loss of dopaminergic neurons in the nigrostriatal system. A lack of heritability for idiopathic PD has implicated adulthood environmental factors in the etiology of the disease. However, compelling evidence from animal models published within the past few years has shown that a range of environmental factors occurring during the perinatal period (including exposure to the common pesticides paraquat and maneb, organochlorine pesticides, and iron-enriched diet) and the prenatal period (including the pesticide maneb, cocaine, and the bacterial product LPS) can either directly cause a reduction in the number of dopamine neurons, or cause an increased susceptibility to degeneration of these neurons with subsequent environmental insults or with aging alone. In this review, these models are described for potential relevance in linking PD with the Fetal Basis of Adult Disease (FeBAD) hypothesis. Additionally, challenges in studying the neurodevelopmental basis of neurodegeneration experimentally and epidemiologically are presented.
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PMID:The gestational environment and Parkinson's disease: evidence for neurodevelopmental origins of a neurodegenerative disorder. 1735 Jul 99

In Alzheimer's disease (AD), Parkinson's disease (PD), dementia with Lewy bodies (DLB) and amyotrophic lateral sclerosis (ALS), neuroinflammatory responses are considered to contribute to neuronal injury. Recently, the innate immune receptors, toll-like receptors (TLRs) and the LPS receptor (CD14) have been related to neurodegeneration. In this study, we systematically assessed the expression of most TLRs and CD14 in AD, PD/DLB and ALS using murine models of these diseases and human post-mortem brain tissues. A common upregulation of TLR2 and CD14 was found in all three animal models. While these two receptors could also be detected in AD patient tissues, they were absent from DLB and ALS tissues. This uniform pattern of innate immune response in animal models of neurodegenerative diseases clearly indicates that this response is part of a non-specific neuroinflammatory effector phase rather than a disease-specific event. The less dynamic disease progression in humans and the location (extracellular versus intracellular) of the aggregated proteins deposits might explain the divergent results seen between animal models and human tissues.
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PMID:Screening of innate immune receptors in neurodegenerative diseases: a similar pattern. 1790 82

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.
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PMID:Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. 1834 32

Using primary rat mesencephalic neuron-glia cultures as an in vitro model of Parkinson's disease (PD), we tested the effect of curcumin, a natural dietary pigment with well-known anti-inflammation effects, on dopaminergic (DA) degeneration. Curcumin pretreatment mitigated LPS-induced DA neurotoxicity in a concentration-dependent manner and curcumin post-treatment also showed protective effect. Microglia depletion abolished this protective effect of curcumin, indicating that microglia play an important role in this effect. Supportively, observation by immunocytochemistry staining using OX-42 antibody showed that curcumin treatment inhibited LPS-induced morphological change of microglia. Besides, LPS-induced production of many proinflammatory factors and their gene expressions decreased dramatically after curcumin treatment. Results also revealed that curcumin treatment decreased LPS-induced activation of two transcription factors--nuclear factors kappaB (NF-kappaB) and activator protein-1 (AP-1). Taken together, our study implicated that curcumin might be a potential preventive and therapeutic strategy for inflammation-related neurodegenerative diseases.
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PMID:Curcumin protects dopaminergic neuron against LPS induced neurotoxicity in primary rat neuron/glia culture. 1836 83

Brain inflammation is a suggested risk factor for neurodegenerative disease. Interestingly, severe inflammation in the substantia nigra pars compacta (SNpc) accelerates the onset and progression of Parkinson's disease. In this study, we examined the underlying mechanisms of severe inflammation in the SNpc by comparing the inflammatory process with that in the cortex. In intact brain, the densities of CD11b(+) microglia were similar in the SNpc and cortex. However, lipopolysaccharide injection enhanced the CD11b(+) cell number in the SNpc, but not in the cortex. Previously, we reported that CD11b and myeloperoxidase (MPO) double-positive neutrophils infiltrate the SNpc following LPS injection (GLIA 55:1577-88). Notably, the MPO(+) neutrophil number increased dramatically in the SNpc, but only slightly in the cortex. The extent of neutrophil infiltration appeared to correlate with neuronal damage. We confirmed that loss of neurons in the SNpc was significantly reduced in neutropenic rats versus normal rats following LPS injection. In addition, the densities of astrocytes were much lower in the intact SNpc, compared with the cortex. Furthermore, after LPS injection, damage of endothelial cells and astrocytes, and blood-brain barrier (BBB) permeability was more pronounced in the SNpc. These results collectively suggest that excessive neutrophil infiltration and environmental factors, such as lower astrocyte density and higher BBB permeability, contribute to severe inflammation and neuronal death in the SNpc.
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PMID:Differential neutrophil infiltration contributes to regional differences in brain inflammation in the substantia nigra pars compacta and cortex. 1838 56

We have previously reported that a single injection of endotoxin, lipopolysaccharide (LPS, 5mg/kg, i.p.), causes a delayed and progressive loss of TH-IR neurons in the substantia nigra (SN) in C57BL/six male mice. In this study, we determined sex differences and behavioral deficits accompanying the loss of TH-IR neurons in response to peripheral LPS injection. A single injection of LPS (5mg/kg, i.p.) failed to produce any loss of TH-IR neurons in the SN of female mice over a 12-month period. To determine if multiple-injections were required, female mice received five injections of LPS (5mg/kg, i.p.) at either weekly or monthly intervals. Behavioral motor ability and TH-IR neuronal loss were determined after the first injection of LPS. We found significant differences in both behavioral activities and neuronal loss between these two injection paradigms. Between 7 and 20 months after the first injection of LPS, progressive behavioral changes, measured by rotor-rod and open-field activities, and neuronal loss in SN were observed in monthly injected, but not in weekly injected mice. In addition, reduced rotor-rod ability in monthly injected mice were restored following treatment of l-dopa/carbidopa (30 mg/3mg/kg), i.p.). Approximately 40 and 50% loss of TH-IR neurons at 9 and 20 months, respectively, was observed after exposure to LPS, suggesting that the behavioral deficit is related to loss of dopamine function in the nigra-striatal pathway. More intense immuno-staining of alpha-synuclein and inflammatory markers were detected in brain sections exposed to LPS. In conclusion, these results show that multi-LPS monthly injections can induce a delayed and progressive loss of TH-IR neurons and motor deficits which resemble the progressive nature of Parkinson's disease. Further, the present study reveals a clear sex difference: female mice are more resistant to LPS than male mice. Repeated monthly LPS injections are required to cause both motor behavioral deficits and DA neuronal loss in female mice.
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PMID:Endotoxin induces a delayed loss of TH-IR neurons in substantia nigra and motor behavioral deficits. 1847 86

Activated microglia produce diverse neurotoxic factors such as nitric oxide (NO) and prostaglandin E(2) (PGE(2)) that may cause neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease. From the EtOAc soluble fraction of Farfarae flos (Tussilago farfara), we purified tussilagone as a bioactive compound by monitoring the inhibitory potential of NO production in activated microglia through the purification procedures. Tussilagone showed dose-dependent inhibition of NO and PGE(2) production in LPS-activated microglia with IC(50) values of 8.67 microM and 14.1 microM, respectively. It suppressed the expression of protein and mRNA of inducible nitric oxide synthase and cyclooxygenase-2 through the inhibition of 1-kappaBalpha degradation and nuclear translocation of p65 subunit of NF-kappaB. Therefore tussilagone from Farfarae flos may have therapeutic potential in the treatment of neuro-inflammatory diseases through the inhibition of overproduction of NO and PGE(2).
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PMID:Suppression of inducible nitric oxide synthase and cyclooxygenase-2 expression by tussilagone from Farfarae flos in BV-2 microglial cells. 1848 Oct 23


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