scholarly journals Uncaria rhynchophylla Ameliorates Parkinson’s Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics

2018 ◽  
Vol 47 (4) ◽  
pp. 1453-1464 ◽  
Author(s):  
Yu-Long Lan ◽  
Jun-Jun Zhou ◽  
Jing Liu ◽  
Xiao-Kui Huo ◽  
Ya-Li Wang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Western Blotting ◽  
Quantitative Proteomics ◽  
Neuroprotective Effect ◽  
Differentially Expressed ◽  
Signal Pathways ◽  
Uncaria Rhynchophylla

Background/Aims: Uncaria rhynchophylla, known as “Gou-teng”, is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP+-induced SH-SY5Y cells and MPTP-induced mice. Methods: MPP+-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson’s disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP+-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. Results: URE dose-dependently increased the cell viability in MPP+-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP+-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨm). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and elevated the positive expressions of TH in SN and STR as well as the TH protein. Conclusions: URE possessed the neuroprotective effect in vivo and in vitro, regulated MAPK and PI3K-AKT signal pathways, and inhibited the expression of HSP90. U. rhynchophylla has potentials as therapeutic agent in PD treatment.

scholarly journals Neuroprotective Effect of Optimized Yinxieling Formula in 6-OHDA-Induced Chronic Model of Parkinson’s Disease through the Inflammation Pathway

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Renrong Wei ◽  
Cuiping Rong ◽  
Qingfeng Xie ◽  
Shouhai Wu ◽  
Yuchao Feng ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Calcium Binding ◽  
Dopaminergic Neurons ◽  
Neuroprotective Effect ◽  
Interleukin 1 ◽  
Mrna Levels ◽  
Cox 2

Parkinson’s disease (PD) is characterized by progressive degeneration of dopaminergic neurons in the substantia nigra (SN)-striatum circuit, which is associated with glial activation and consequent chronic neuroinflammation. Optimized Yinxieling Formula (OYF) is a Chinese medicine that exerts therapeutical effect and antiinflammation property on psoriasis. Our previous study has proven that pretreatment with OYF could regulate glia-mediated inflammation in an acute mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Given that PD is a chronic degeneration disorder, this study applied another PD animal model induced by striatal injection of 6-hydroxydopamine (6-OHDA) to mimic the progressive damage of the SN-striatum dopamine system in rats. The OYF was administrated in the manner of pretreatment plus treatment. The effects of the OYF on motor behaviors were assessed with the apomorphine-induced rotation test and adjusting steps test. To confirm the effect of OYF on dopaminergic neurons and glia activation in this model, we analyzed the expression of tyrosine hydroxylase (TH) and glia markers, ionized calcium-binding adapter molecule 1 (Iba-1), and glial fibrillary acidic protein (GFAP) in the SN region of the rat PD model. Inflammation-associated factors, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), were further evaluated in this model and in interferon-γ- (INF-γ-) induced murine macrophages RAW264.7 cells. The results from the in vivo study showed that OYF reversed the motor behavioral dysfunction in 6-OHDA-induced PD rats, upregulated the TH expression, decreased the immunoreactivity of Iba-1 and GFAP, and downregulated the mRNA levels of TNF-α and COX-2. The OYF also trended to decrease the mRNA levels of IL-1β and iNOS in vivo. The results from the in vitro study showed that OYF significantly decreased the mRNA levels of TNF-α, IL-1β, IL-6, iNOS, and COX-2. Therefore, this study suggests that OYF exerts antiinflammatory effects, which might be related to the protection of dopaminergic neurons in 6-OHDA-induced chronic neurotoxicity.

Calcium Channels as a Potential Target for Neuroprotection in Parkinson’s Disease

US Neurology ◽  
2011 ◽  
Vol 07 (02) ◽  
pp. 109 ◽  
Author(s):  
Tanya Simuni ◽  
D James Surmeier ◽  
◽  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuroprotective Effect ◽  
Selective Vulnerability ◽  
Phase Iii ◽  
Substantia Nigra Pars Compacta ◽  
Double Blind ◽  
Finding Study

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting 1 % of the population above the age 65. The principal motor symptoms of PD are attributable to the preferential loss of dopaminergic neurons in the substantia nigra pars compacta (SNc). Recent studies demonstrate that dopaminergic (DA) neurons in the SNc, as well as many neurons in other regions affected by PD, have a distinctive physiologic phenotype. They are autonomous L-type Cav1.3 Ca2+channels pacemakers. Continuous Ca2+influx results in increased oxidative stress that may explain the selective vulnerability of these neurons. More importantly for PD, blocking these channels with isradipine, the most potent of the dihydropyridine (DHP) channel antagonists at L-type Ca2+channels with the Cav1.3 subunit, protects these neurons inin vitroandin vivomodels of parkinsonism. Neuroprotective effect is achieved at the serum concentrations that can be achieved with the doses approved for human use. Recent epidemiologic data also points to a reduced risk of PD with chronic use of specifically centrally acting DHP Ca2+channel antagonists. Isradipine is an approved agent for the treatment of hypertension. Our pilot data demonstrate acceptable dose-dependent tolerability of isradipine in early PD. A pilot Phase II multicenter, double-blind, placebo-controlled, safety, tolerability, and dosage finding study of isradipine in early PD has completed recruitment, with the results of the study to be available in the near future. Results of that study will inform the design of the planned Phase III pivotal efficacy trial of isradipine, as a disease modifying agent in early PD.

scholarly journals A Novel Synthetic Precursor of Styryl Sulfone Neuroprotective Agents Inhibits Neuroinflammatory Responses and Oxidative Stress Damage through the P38 Signaling Pathway in the Cell and Animal Model of Parkinson’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (17) ◽  
pp. 5371
Author(s):  
Ying Guo ◽  
Zhizhong Ma ◽  
Xianling Ning ◽  
Ying Chen ◽  
Chao Tian ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Inflammatory Responses ◽  
Neuroprotective Effect ◽  
Detoxification Enzymes ◽  
Mitogen Activated Protein Kinase ◽  
Related Factor ◽  
Apoptosis Pathway

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson’s disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.

scholarly journals Neuroprotective Effect of the Marine-Derived Compound 11-Dehydrosinulariolide through DJ-1-Related Pathway in In Vitro and In Vivo Models of Parkinson’s Disease

Marine Drugs ◽  
2016 ◽  
Vol 14 (10) ◽  
pp. 187 ◽  
Author(s):  
Chien-Wei Feng ◽  
Han-Chun Hung ◽  
Shi-Ying Huang ◽  
Chun-Hong Chen ◽  
Yun-Ru Chen ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neuroprotective Effect ◽  
In Vivo Models ◽  
Related Pathway

scholarly journals The Involvement of Neuroinflammation and Kynurenine Pathway in Parkinson's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-11 ◽  
Author(s):  
Anna Zinger ◽  
Carlos Barcia ◽  
Maria Trinidad Herrero ◽  
Gilles J. Guillemin
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Dopaminergic Neurons ◽  
Therapeutic Strategy ◽  
Neurodegenerative Disorder ◽  
Neuroprotective Effect ◽  
Kynurenine Pathway ◽  
Receptor Signalling

Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms. Activated microglia themselves release a large number of inflammatory mediators thus perpetuating neuroinflammation and neurotoxicity. The Kynurenine pathway (KP), the main catabolic pathway for tryptophan, is one of the major regulators of the immune response and may also be implicated in the inflammatory response in parkinsonism. The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. Several of these molecules produced by microglia can activate the N-methyl-D-aspartate (NMDA) receptor-signalling pathway, leading to an excitotoxic response. Previous studies have shown that NMDA antagonists can ease symptoms and exert a neuroprotective effect in PD bothin vivoandin vitro. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD.

MicroRNA-181a-5p Down-Regulation Presents Neuroprotective Effect in 1-Methyl-4-Phenylpyridinium-Induced Parkinson’s Disease: An In Vitro Study

2020 ◽  
Vol 10 (1) ◽  
pp. 63-70
Author(s):  
YanLi Guo ◽  
Xu Hua
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cell Viability ◽  
Western Blotting ◽  
Neuroprotective Effect ◽  
C6 Cells ◽  
Down Regulation ◽  
Qrt Pcr ◽  
Ldh Activity

Background: Parkinson’s disease (PD) is a long-term degenerative disease that mainly affects the central nervous system of the motor system. MicroRNA-181a-5p (miR-181a-5p) is well studied a variety of malignancies. But, till now, there is no report of the role of miR-181a-5p in PD. Methods: miR-181a-5p level was detected using quantitative reverse transcription polymerase chain reaction (qRT-PCR), and western blotting analysis/qRT-PCR was used to measure the level of Sirtuin 1 (SIRT1). We evaluated cell viability and apoptosis using 3-(4,5-dimethyl thiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry (FCM), and used enzyme linked immunosorbent assay (ELISA) assay to examine the releases of inflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α. Commercially available kits was applied to assess the lactate dehydrogenase (LDH) activity. Western blotting analyse was used to detect nuclear factor-κB p65 (NF-κB p65) and phosphorylated (p)-p65 protein expression. TargetScan and Dual luciferase reporter assay were carried out to determine the interaction between miR-181a-5p and SIRT1. Results: Results showed that miR-181a-5p was up-regulated and SIRT1 was down-regulated in MMP+-treated C6 cells. miR-181a-5p knockdown attenuated the neurotoxicity induced by MMP+-treatment in C6 cells, evidenced by the enhancement of C6 cell viability, and the suppression of C6 cell apoptosis, LDH activity and inflammation. SIRT1 was found as a direct target of miR-181a-5p, and all these effects of miR-181a-5p inhibition on MMP+-treated C6 cells were reversed by SIRT1 knockdown. Conclusion: Our data suggested that miR-181a-5p down-regulation presents neuroprotective effect in MMP+-induced PD in vitro model by targeting SIRT1.

Neuroprotective Effect of Coptis chinensis in MPP+ and MPTP-Induced Parkinson’s Disease Models

2016 ◽  
Vol 44 (05) ◽  
pp. 907-925 ◽  
Author(s):  
Thomas Friedemann ◽  
Yue Ying ◽  
Weigang Wang ◽  
Edgar R. Kramer ◽  
Udo Schumacher ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Diseases ◽  
Cell Model ◽  
Neuroprotective Effect ◽  
Treatment Options ◽  
Coptis Chinensis

The rhizome of Coptis chinensis is commonly used in traditional Chinese medicine alone or in combination with other herbs to treat diseases characterized by causing oxidative stress including inflammatory diseases, diabetes mellitus and neurodegenerative diseases. In particular, there is emerging evidence that Coptis chinensis is effective in the treatment of neurodegenerative diseases associated with oxidative stress. Hence, the aim of this study was to investigate the neuroprotective effect of Coptis chinensis in vitro and in vivo using MPP[Formula: see text] and MPTP models of Parkinson’s disease. MPP[Formula: see text] treated human SH-SY5Y neuroblastoma cells were used as a cell model of Parkinson’s disease. A 24[Formula: see text]h pre-treatment of the cells with the watery extract of Coptis chinensis significantly increased cell viability, as well as the intracellular ATP concentration and attenuated apoptosis compared to the MPP[Formula: see text] control. Further experiments with the main alkaloids of Coptidis chinensis, berberine, coptisine, jaterorrhizine and palmatine revealed that berberine and coptisine were the main active compounds responsible for the observed neuroprotective effect. However, the full extract of Coptis chinensis was more effective than the tested single alkaloids. In the MPTP-induced animal model of Parkinson’s disease, Coptis chinensis dose-dependently improved motor functions and increased tyrosine hydroxylase-positive neurons in the substantia nigra compared to the MPTP control. Based on the results of this work, Coptis chinensis and its main alkaloids could be considered potential candidates for the development of new treatment options for Parkinson’s disease.

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