Synergistic effects of ceftriaxone and erythropoietin on neuronal and behavioral deficits in an MPTP-induced animal model of Parkinson’s disease dementia

2015 ◽  
Vol 294 ◽  
pp. 198-207 ◽  
Author(s):  
Chiu-Ku Huang ◽  
Yen-Ting Chang ◽  
Tamara G. Amstislavskaya ◽  
Maria A. Tikhonova ◽  
Chih-Li Lin ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Synergistic Effects ◽  
Parkinson’S Disease Dementia ◽  
Behavioral Deficits

scholarly journals Synergistic effect of combined GDNF and Amodiaquine attenuates behavioral deficits and protect dopaminergic neurons of Parkinson’s disease animal model through tyrosine kinase Ret receptor

2020 ◽  
Author(s):  
Piniel Kambey ◽  
Dianshuai Gao
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Tyrosine Kinase ◽  
Cell Line ◽  
Neurotrophic Factor ◽  
Dopaminergic Neurons ◽  
Combined Therapy ◽  
Behavioral Deficits ◽  
Neuro Protection

Abstract Parkinson’s disease (PD) is one among the most leading neurodegenerative disease after Alzheimer’s disease, with a prevalence of approximately 0.5–1% among those 65–69 years of age. Efforts to vitiate this disease are ongoing, and several treatment modes such as Glial cell line-derived neurotrophic factor (GDNF) have been in place since 1993. Glial cell line derived neurotrophic factor (GDNF) protects, regenerates, and improves the metabolism of substantia nigra pars compacta neurons (SNpc), and it increases the high-affinity dopamine uptake. It has been recently reported that amodiquine could attenuates the behavioral deficits of an animal model of Parkinson’s disease, nevertheless it mechanism is obscure. We sought to demonstrate the mechanism of neuro-protection effect of amodiquine and ascertain its corroborative effect when used togather with GDNF. We show herein that combined therapy (GDNF and amodiaquine) ameliorated behavioral deficits of PD animal models as compared to single-factor treatment. TH positive neurons increased significantly upon combined therapy treatment, and besides, GDNF and amodiaquine interact functionally to protect dopaminergic neurons through the PIK-3/Akt pathway. We also found that combined therapy (GDNF and amodiaquine) mediates its action through a distinct trans-membrane tyrosine kinase Ret receptor by amplifying its effect. Slight elevated aspartate aminotransferase (AST) were noticed in amodiaquine treated groups, alarming the bio-utility. These findings collectively suggest an interplay between GDNF and amodiaquine and co-express to exert neuronal protection hence a promising approach in PD therapy. Despite its undisputed effect on neuro-protection, we report that amodiaquine may not be safe, particularly in translation to human beings' trial settings.

scholarly journals Parkinson’s Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron

2021 ◽  
Vol 13 ◽  
Author(s):  
Jiajun Han ◽  
Yaohua Fan ◽  
Peipei Wu ◽  
Zifeng Huang ◽  
Xinrong Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Glycogen Synthase ◽  
Synergistic Effects ◽  
Beta Amyloid ◽  
Alpha Synuclein ◽  
Protein Accumulation ◽  
Vicious Cycle ◽  
Parkinson’S Disease Dementia ◽  
Post Translational Modification

Parkinson’s disease dementia (PDD) is a common complication of Parkinson’s disease that seriously affects patients’ health and quality of life. At present, the process and pathological mechanisms of PDD remain controversial, which hinders the development of treatments. An increasing number of clinical studies have shown that alpha-synuclein (α-syn), tau, beta-amyloid (Aβ), and iron are closely associated with PDD severity. Thus, we inferred the vicious cycle that causes oxidative stress (OS), due to the synergistic effects of α-syn, tau, Aβ, and, iron, and which plays a pivotal role in the mechanism underlying PDD. First, iron-mediated reactive oxygen species (ROS) production can lead to neuronal protein accumulation (e.g., α-syn andAβ) and cytotoxicity. In addition, regulation of post-translational modification of α-syn by iron affects the aggregation or oligomer formation of α-syn. Iron promotes tau aggregation and neurofibrillary tangles (NFTs) formation. High levels of iron, α-syn, Aβ, tau, and NFTs can cause severe OS and neuroinflammation, which lead to cell death. Then, the increasing formation of α-syn, Aβ, and NFTs further increase iron levels, which promotes the spread of α-syn and Aβ in the central and peripheral nervous systems. Finally, iron-induced neurotoxicity promotes the activation of glycogen synthase kinase 3β (GSK3β) related pathways in the synaptic terminals, which in turn play an important role in the pathological synergistic effects of α-syn, tau and Aβ. Thus, as the central factor regulating this vicious cycle, GSK3β is a potential target for the prevention and treatment of PDD; this is worthy of future study.

Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson's disease dementia

2015 ◽  
Vol 91 ◽  
pp. 43-56 ◽  
Author(s):  
Chao-Yu Hsu ◽  
Ching-Sui Hung ◽  
Hung-Ming Chang ◽  
Wen-Chieh Liao ◽  
Shih-Chun Ho ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Animal Model ◽  
Parkinson’S Disease Dementia

scholarly journals Neuroinflammation and protein pathology in Parkinson’s disease dementia

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Antonina Kouli ◽  
Marta Camacho ◽  
Kieren Allinson ◽  
Caroline H. Williams-Gray
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
T Lymphocytes ◽  
Substantia Nigra ◽  
Amyloid Β ◽  
Brain Regions ◽  
Parkinson’S Disease Dementia ◽  
Activated Microglia ◽  
Cell Counts ◽  
The Brain

AbstractParkinson’s disease dementia is neuropathologically characterized by aggregates of α-synuclein (Lewy bodies) in limbic and neocortical areas of the brain with additional involvement of Alzheimer’s disease-type pathology. Whilst immune activation is well-described in Parkinson’s disease (PD), how it links to protein aggregation and its role in PD dementia has not been explored. We hypothesized that neuroinflammatory processes are a critical contributor to the pathology of PDD. To address this hypothesis, we examined 7 brain regions at postmortem from 17 PD patients with no dementia (PDND), 11 patients with PD dementia (PDD), and 14 age and sex-matched neurologically healthy controls. Digital quantification after immunohistochemical staining showed a significant increase in the severity of α-synuclein pathology in the hippocampus, entorhinal and occipitotemporal cortex of PDD compared to PDND cases. In contrast, there was no difference in either tau or amyloid-β pathology between the groups in any of the examined regions. Importantly, we found an increase in activated microglia in the amygdala of demented PD brains compared to controls which correlated significantly with the extent of α-synuclein pathology in this region. Significant infiltration of CD4+ T lymphocytes into the brain parenchyma was commonly observed in PDND and PDD cases compared to controls, in both the substantia nigra and the amygdala. Amongst PDND/PDD cases, CD4+ T cell counts in the amygdala correlated with activated microglia, α-synuclein and tau pathology. Upregulation of the pro-inflammatory cytokine interleukin 1β was also evident in the substantia nigra as well as the frontal cortex in PDND/PDD versus controls with a concomitant upregulation in Toll-like receptor 4 (TLR4) in these regions, as well as the amygdala. The evidence presented in this study show an increased immune response in limbic and cortical brain regions, including increased microglial activation, infiltration of T lymphocytes, upregulation of pro-inflammatory cytokines and TLR gene expression, which has not been previously reported in the postmortem PDD brain.

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