scholarly journals Intranigral Administration of β-Sitosterol-β-D-Glucoside Elicits Neurotoxic A1 Astrocyte Reactivity and Chronic Neuroinflammation in the Rat Substantia Nigra

2020 ◽  
Vol 2020 ◽  
pp. 1-19
Author(s):  
Claudia Luna-Herrera ◽  
Irma A. Martínez-Dávila ◽  
Luis O. Soto-Rojas ◽  
Yazmin M. Flores-Martinez ◽  
Manuel A. Fernandez-Parrilla ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Immune Cell ◽  
Reactive Astrocytes ◽  
No Production ◽  
Acute Administration ◽  
Activated Microglia ◽  
Chronic Neuroinflammation ◽  
Tnf Α

Chronic consumption of β-sitosterol-β-D-glucoside (BSSG), a neurotoxin contained in cycad seeds, leads to Parkinson’s disease in humans and rodents. Here, we explored whether a single intranigral administration of BSSG triggers neuroinflammation and neurotoxic A1 reactive astrocytes besides dopaminergic neurodegeneration. We injected 6 μg BSSG/1 μL DMSO or vehicle into the left substantia nigra and immunostained with antibodies against tyrosine hydroxylase (TH) together with markers of microglia (OX42), astrocytes (GFAP, S100β, C3), and leukocytes (CD45). We also measured nitric oxide (NO), lipid peroxidation (LPX), and proinflammatory cytokines (TNF-α, IL-1β, IL-6). The Evans blue assay was used to explore the blood-brain barrier (BBB) permeability. We found that BSSG activates NO production on days 15 and 30 and LPX on day 120. Throughout the study, high levels of TNF-α were present in BSSG-treated animals, whereas IL-1β was induced until day 60 and IL-6 until day 30. Immunoreactivity of activated microglia ( 899.0 ± 80.20 % ) and reactive astrocytes ( 651.50 ± 11.28 % ) progressively increased until day 30 and then decreased to remain 251.2 ± 48.8 % (microglia) and 91.02 ± 39.8 (astrocytes) higher over controls on day 120. C3(+) cells were also GFAP and S100β immunoreactive, showing they were neurotoxic A1 reactive astrocytes. BBB remained permeable until day 15 when immune cell infiltration was maximum. TH immunoreactivity progressively declined, reaching 83.6 ± 1.8 % reduction on day 120. Our data show that BSSG acute administration causes chronic neuroinflammation mediated by activated microglia, neurotoxic A1 reactive astrocytes, and infiltrated immune cells. The severe neuroinflammation might trigger Parkinson’s disease in BSSG intoxication.

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.

scholarly journals Effect of n-3 polyunsaturated fatty acids on dopaminergic neurons in substantia nigra, brain inflammatory response and behavior in mice with Parkinson’s disease

2021 ◽  
Vol 18 (4) ◽  
pp. 767-772
Author(s):  
Zhaowen Zhang ◽  
Sisi Wang ◽  
Chengyan Li
Keyword(s):  
Parkinson’S Disease ◽  
Fatty Acids ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Inflammatory Response ◽  
Polyunsaturated Fatty Acids ◽  
Normal Control ◽  
Dopaminergic Neurons ◽  
Tnf Α ◽  
Ifn Γ

Purpose: To examine the effect of n-3 polyunsaturated fatty acids (PUFAs) on dopaminergic neurons in substantia nigra, intracerebral inflammatory response and ethology in mice with Parkinson’s disease (PD). Methods: Four groups of male C57BL/6 mice (n = 48) were used: normal control, negative control, n3PUFA, and Madopa groups. Except for normal control group, all groups were given 6- hydroxydopamine hydrochloride (6-OHDA) to establish Parkinson’s mice model. The expressions of tyrosine hydroxylase (TH) and calcium-binding protein (CB) in substantia nigra dopaminergic neurons were determined with immunohistochemistry and Western blot. The contents of nitric oxide (NO), tumor necrosis factor (TNF-α) and interferon γ (IFN-γ) (indices of intracerebral inflammatory response) were measured. Tremor paralysis, moving grid number, standing times, swimming ability, and the number of rollers in each group were observed as indices of ethology. Results: The number of TH and CB-positive neurons in the substantia nigra of n-3PUFA-treated mice was significantly increased, relative to those in Madopa-treated mice (p < 0.05). The expressions of TH and CB proteins in substantia nigra in n-3PUFA group were markedly higher than the corresponding expressions in Madopa-treated mice (p < 0.05). Decreased levels of NO, TNF-α and IFN-γ levels were seen in 3PUFA group, when compared to mice in Madopa group, but higher behavioral scores were obtained in n-3PUFA-treated mice, relative to Madopa-treated mice (p < 0.05). Conclusion: The n-3PUFAs protect substantia nigra compact dopaminergic neurons against Parkinson’s disease, alleviate immune inflammation, and improve the coordination of limb movement. Thus, n-3PUFAs have potential therapeutic application in the management of Parkinson’s disease.

Neuroinflammation caused by activated microglia and astrocytes can contribute to the progression of pathogenic damage to substantia nigra neurons, playing a role in Parkinson's disease progression

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Oxidative Stress ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Mitochondrial Dysfunction ◽  
Dopaminergic Neurons ◽  
Molecular Mechanisms ◽  
High Energy ◽  
Molecular Pathways ◽  
Activated Microglia

Parkinson's disease progresses by a number of regionally specific cellular and molecular mechanisms. Furthermore, these pathways interact and have an influence on one another in both normal and pathological conditions. Neuroinflammation caused by activated microglia and astrocytes can contribute to the progression of pathogenic damage to substantia nigra (SN) neurons. Similarly, oxidative stress may be caused by a variety of stressors, such as contaminants in the environment or age-related mitochondrial dysfunction, leading to the production of reactive oxygen species (ROS). Dopamine auto-oxidation is a significant generator of ROS in dopaminergic neurons, resulting in neuronal oxidative stress. The high energy demands of dopaminergic neurons may result in mitochondrial dysfunction and oxidative damage as they age. Because mitophagy clears dysfunctional mitochondria from SN neurons, mutation-related abnormalities in autophagy of defective proteins might allow damaging proteins to accumulate in the cell. Because the effects of aging on these molecular pathways and cellular activities are unknown, further study into these molecular pathways and their connections in normal and sick states will be essential for developing disease-specific therapies.

Extract of Tripterygium wilfordii Hook F Protect Dopaminergic Neurons Against Lipopolysaccharide-Induced Inflammatory Damage

2010 ◽  
Vol 38 (04) ◽  
pp. 801-814 ◽  
Author(s):  
Yuxin Liu ◽  
Hui-Ling Chen ◽  
Gengliang Yang
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Neurodegenerative Disease ◽  
Dopaminergic Neurons ◽  
Chinese Herbs ◽  
No Production ◽  
Tripterygium Wilfordii ◽  
Tripterygium Wilfordii Hook F ◽  
Activated Microglia ◽  
Tripterygium Wilfordii Hook

Activation of microglia is a critical pathological marker of Parkinson's disease. Activated microglia produces proinflammatory and neurotoxic factors, which cause neurons to induce neurodegeneration. Although it is believed that Chinese herbs, such as Tripterygium wilfordii Hook F, can ease inflammatory diseases, little is known about its benefit to neurodegenerative disease, like Parkinson's disease. In this study, we report the extract of Tripterygium wilfordii Hook F with a novel extraction method significantly protected dopaminergic neurons from LPS-induced degeneration in rat mesencephalic neuron-glia cultures. Cells pretreated with the extract have shown dose-dependent inhibition of LPS-induced TNFα and excessive NO production. More importantly, the total number of activated microglia was greatly reduced in these pretreated cells. Our results suggest that the extract of Tripterygium wilfordii Hook F has a strong bioactive function to diminish the pro-inflammatory factors, such as TNFα and NO. These data might also shed light for future neurodegenerative disease therapy.

scholarly journals Repressing PTB is incapable to convert reactive astrocytes to dopaminergic neurons in a mouse model of Parkinson's disease

2021 ◽  
Author(s):  
Weizhao Chen ◽  
Qiongping Zheng ◽  
Qiaoying Huang ◽  
Shanshan Ma ◽  
Mingtao Li
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Dopaminergic Neurons ◽  
Lineage Tracing ◽  
Reactive Astrocytes ◽  
Reactive Astrocyte ◽  
Adeno Associated Virus ◽  
Polypyrimidine Tract Binding Protein ◽  
Tracing Method

Lineage reprograming of resident glia cells to induced dopaminergic neurons (iDAns) holds attractive prospect for cell-replacement therapy of Parkinson's disease (PD). Recently, whether repressing polypyrimidine tract binding protein (PTB) could truly achieve efficient astrocyte-to-iDAn conversion in substantia nigra and striatum aroused widespread controversy. Although reporter+ iDAns were observed by two groups after delivering adeno-associated virus (AAV) expressing a reporter with shRNA or Crispr-CasRx to repress astroglial PTB, the possibility of AAV leaking into endogenous DAns could not be excluded without using a reliable lineage tracing method. By adopting stringent lineage tracing strategy, two other studies showed that neither knockdown nor genetic deletion of quiescent astroglial PTB fails to obtain iDAns under physiological condition. However, the role of reactive astrocyte might be underestimated since upon brain injury, reactive astrocyte could acquire certain stem cell hallmarks which may facilitate the lineage conversion process. Therefore, whether reactive astrocytes could be genuinely converted to DAns after PTB repression in a PD model needs further validation. In this study, we used Aldh1l1-CreERT2-mediated specific astrocyte-lineage tracing method to investigate whether reactive astrocytes could be converted to DAns in the 6-OHDA PD model. However, we found that no astrocyte-originated DAns was generated after effective knockdown of astroglial PTB either in the substantia nigra or in the striatum, while AAV leakage to nearby neurons was observed. Our results further confirmed that repressing PTB is unable to convert astrocytes to DA neurons no matter in physiological or PD-related pathological conditions.

Hyperechogenicity of substantia nigra in Parkinson's disease – Searching for genetic predictors

2008 ◽  
Vol 35 (S 01) ◽  
Author(s):  
C Funke ◽  
A Soehn ◽  
C Schulte ◽  
M Bonin ◽  
C Klein ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Substantia Nigra ◽  
Genetic Predictors
Sign in / Sign up

Export Citation Format

Share Document