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Effect of Ginsenoside RD on Lipopolysaccharide-Induced Neuroinflammation in Dopaminergic Cell Culture

Author: LinZuoMing
Tutor: ZhangYanMing;Wolf-Dieter Rausch
School: Northwest University of Science and Technology
Course: Preventive Veterinary Medicine
Keywords: dopaminergic lipopolysaccharide ginsenoside Rd neuroinflammation
CLC: R285.5
Type: PhD thesis
Year: 2007
Downloads: 229
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Abstract


Several mechanisms of cytotoxicity have been hypothesized to underlie the death of dopaminergic neurons in the substantia nigra (SN) in patients with Parkinson’s disease (PD) including apoptosis, oxidative stress and mitochondrial dysfunction. Recently, clinical and experimental evidences suggest that neuroinflammatory changes caused by microglial activation contribute to neuronal degeneration. Experimentally, neuroinflammation of dopaminergic neurons can be evoked by lipopolysaccharides (LPS) exposure. An effective anti-inflammatory therapy should not only alleviate the disease-associated symptoms, but also interfere with glial reactions, an increase in inflammatory factors and progressive dopaminergic cell death. This study focusses on LPS-induced glial overactivation, overproduction inflammatory factors and efficacy of ginsenoside Rd in dopminergic cell culture. The results as following:1.Mesencephalic primary cultures were employed in this study. Results showed that LPS destroyed TH+ neurons in a dose-dependent manner (50-400μg/ml) and LPS (100μg/ml) resulted in 30-50 % loss of TH+ cells. LPS equally affected others neural cells (such as astroglia and NeuN+ neurons) in these mixed neuronal-glial cultures. Changes in morphology of dopaminergic neurons were manifested in losses of dendritic processes and branching and deterioration of cell shape and nuclei. LPS from Salmonella typhimurium displayed even higher toxicity. As an inflammatory parameter, there was a dose-dependent increase in NO formation with LPS concentrations ranging from 6.25 to 200μg/ml that reached a peak with 200μg/ml of LPS. PGE2 activity was increased dose dependently reflecting an increase in iNOS.2.Ginsenosides, as the active compounds responsible for ginseng action are reported to have antioxidant and anti-inflammatory effects. Ginsenoside Rd was chosen for its ability to affect NO-concentrations. In this study partial reduction of LPS neurotoxic action by ginsenoside Rd was seen in dopaminergic neurons. Ginsenoside Rd (1-50μmol/L) exerted a significant neuroprotective effect on dopaminergic neurons (123.1%, 127.7% with 1 and 10μmol/L,respectively) compared to cultures treated with LPS. Cell death by LPS as well as neuroprotective action by ginsenoside Rd was not selective for dopaminergic neurons as neuronal losses and cytoprotective effects were similar when counting NeuN identified neurons. Co-incubation of ginsenoside Rd at 1 and 50μmol/L could inhibit the production of LPS-stimulated NO in a concentration-dependent manner, and ginsenoside Rd at 1 and 10μM significantly attenuated the LPS-induced PGE2 production.3.In additional experiments, the effect of a NSAIDs compound indomethacin was tested in comparison. This compound also caused a partial reduction of NO-levels in the supernatant of LPS damaged cell cultures. Additionally drugs which are used for PD medication were tested. L-DOPA as the gold standard of PD treatment gave reductions of NO-levels. Including a dopamine agonist bromocriptine also a partial reversion of NO-levels was observed which coincided with partial sparing of LPS-intoxicated neurons.In conclusion our results suggest that LPS induced dopaminergic neurodegeneration. Activated glial produce free radical such as NO and ONOO- appear to be the major mediators of neurotoxicity. Furthermore, COX-2 induction and PGE2 -increases may also be involved in dopaminergic cell degeneration. The protective mechanisms of ginsenoside Rd could include anti-inflammatory interference with iNOS and COX-2 expression. Other effects as antioxidant and radical scavenging effects have additionally to be considered. As for the positive effects of L-DOPA and bromocriptine either additional stimulation of dopamine receptors or partially non-specific effets (e.g.chelating properties) could be of relevance.

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