Proanthocyanidins exert a neuroprotective effect via ROS/JNK signaling in MPTP‑induced Parkinson's disease models in�vitro and in�vivo

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.

Download Full-text

Squamosamide derivative FLZ protected dopaminergic neuron by activating Akt signaling pathway in 6-OHDA-induced in vivo and in vitro Parkinson's disease models

Brain Research ◽

10.1016/j.brainres.2013.12.026 ◽

2014 ◽

Vol 1547 ◽

pp. 49-57 ◽

Cited By ~ 17

Author(s):

Xiu-Qi Bao ◽

Xiang-Chen Kong ◽

Li-Bing Kong ◽

Liang-Yu Wu ◽

Hua Sun ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Signaling Pathway ◽

Dopaminergic Neuron ◽

Akt Signaling ◽

Disease Models ◽

Akt Signaling Pathway

Download Full-text

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

US Neurology ◽

10.17925/usn.2011.07.02.109 ◽

2011 ◽

Vol 07 (02) ◽

pp. 109 ◽

Cited By ~ 1

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.

Download Full-text

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 ◽

10.3390/molecules26175371 ◽

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.

Download Full-text