Diosgenin Prevents Microglial Activation and Protects Dopaminergic Neurons from Lipopolysaccharide-Induced Neural Damage In Vitro and In Vivo

Background: The prevention of age-related neurodegenerative disorders is an important issue in an aging society. Microglia-mediated neuroinflammation resulting in dopaminergic neuron loss may lead to the pathogenesis of Parkinson’s disease (PD). Lipopolysaccharide (LPS), an endotoxin, induces neuroinflammatory microglial activation, contributing to dopaminergic neuron damage. Diosgenin is a phytosteroid sapogenin with a wide spectrum of pharmacological activities, e.g., anti-inflammatory activity. However, the preventive effect of diosgenin on neuroinflammation is not clear. Thus, in this study, we further investigated the neuroprotective effect of diosgenin on LPS-induced neural damage in vitro and in vivo. Methods: For in vitro experiments, primary mesencephalic neuron-glia cultures and primary microglia cultures isolated from Sprague–Dawley rats were used. Cells were pretreated with diosgenin and then stimulated with LPS. The expression of proinflammatory cytokines or tyrosine hydroxylase (TH) in the cells was analyzed. In vivo, rats were fed a diet containing 0.1% (w/w) diosgenin for 4 weeks before being administered a unilateral substantia nigra (SN) injection of LPS. Four weeks after the LPS injection, the rats were assessed for lesion severity using the amphetamine-induced rotation test and TH immunohistochemistry. Results: Diosgenin pretreatment prevented LPS-induced neurite shortening in TH-positive neurons in mesencephalic neuron-glia cultures. In addition, pretreatment of primary microglia with diosgenin significantly reduced tumor necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS) expression. Moreover, diosgenin pretreatment significantly suppressed LPS-induced extracellular signal-regulated kinase (ERK) activation. In vivo, the intranigral injection of LPS in rats fed a diosgenin-containing diet significantly improved motor dysfunction and reduced TH expression in SN. Conclusion: These results support the effectiveness of diosgenin in protecting dopaminergic neurons from LPS-induced neuroinflammation.

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

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2529641 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 1

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.

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A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson’s Disease

Parkinson s Disease ◽

10.1155/2012/364684 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Shankar J. Chinta ◽

Subramanian Rajagopalan ◽

Abirami Ganesan ◽

Julie K. Andersen

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Microglial Activation ◽

Nitrosative Stress ◽

Neurodegenerative Disorder ◽

Oxidative And Nitrosative Stress ◽

Prolyl Hydroxylases ◽

Age Related

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB’s ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cellsin vitroin conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction.In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB’s neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1.

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DHEA Attenuates Microglial Activation via Induction of JMJD3 in Experimental Subarachnoid Haemorrhage

Journal of Neuroinflammation ◽

10.1186/s12974-019-1641-y ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 7

Author(s):

Tao Tao ◽

Guang-Jie Liu ◽

Xuan Shi ◽

Yan Zhou ◽

Yue Lu ◽

...

Keyword(s):

Subarachnoid Haemorrhage ◽

Microglial Activation ◽

Neuronal Damage ◽

Neuroprotective Effect ◽

Early Brain Injury ◽

Protective Effects ◽

In Vivo Models ◽

The Brain

Abstract Background Microglia are resident immune cells in the central nervous system and central to the innate immune system. Excessive activation of microglia after subarachnoid haemorrhage (SAH) contributes greatly to early brain injury, which is responsible for poor outcomes. Dehydroepiandrosterone (DHEA), a steroid hormone enriched in the brain, has recently been found to regulate microglial activation. The purpose of this study was to address the role of DHEA in SAH. Methods We used in vivo models of endovascular perforation and in vitro models of haemoglobin exposure to illustrate the effects of DHEA on microglia in SAH. Results In experimental SAH mice, exogenous DHEA administration increased DHEA levels in the brain and modulated microglial activation. Ameliorated neuronal damage and improved neurological outcomes were also observed in the SAH mice pretreated with DHEA, suggesting neuronal protective effects of DHEA. In cultured microglia, DHEA elevated the mRNA and protein levels of Jumonji d3 (JMJD3, histone 3 demethylase) after haemoglobin exposure, downregulated the H3K27me3 level, and inhibited the transcription of proinflammatory genes. The devastating proinflammatory microglia-mediated effects on primary neurons were also attenuated by DHEA; however, specific inhibition of JMJD3 abolished the protective effects of DHEA. We next verified that DHEA-induced JMJD3 expression, at least in part, through the tropomyosin-related kinase A (TrkA)/Akt signalling pathway. Conclusions DHEA has a neuroprotective effect after SAH. Moreover, DHEA increases microglial JMJD3 expression to regulate proinflammatory/anti-inflammatory microglial activation after haemoglobin exposure, thereby suppressing inflammation.

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Neuroprotective Effect and Mechanism of Thiazolidinedione on Dopaminergic Neurons In Vivo and In Vitro in Parkinson’s Disease

PPAR Research ◽

10.1155/2017/4089214 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 14

Author(s):

Yanqin Wang ◽

Weilin Zhao ◽

Ge Li ◽

Jinhu Chen ◽

Xin Guan ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Neuroprotective Effect ◽

Oral Treatment ◽

Treated Group ◽

Control Group ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Respiratory Factor

The aim of the present study was to gain insight into the neuroprotection effects and mechanism of thiazolidinedione pioglitazone in both in vitro and in vivo MPP+/MPTP induced PD models. In vivo experimental results showed that oral treatment of pioglitazone resulted in significant improvements in behavior symptoms damaged by MPTP and increase in the survival of TH positive neurons in the pioglitazone intervention groups. In addition, oral treatment of pioglitazone increased the expression of peroxisome proliferator-activated receptor-γ coactivator of 1α (PGC-1α) and increased the number of mitochondria, along with an observed improvement in mitochondrial ultrastructure. From in vitro studies, 2,4-thiazolidinedione resulted in increased levels of molecules regulated function of mitochondria, including PGC-1α, nuclear respiratory factor 1 (NRF1), NRF2, and mitochondria fusion 2 (Mfn2), and inhibited mitochondria fission 1 (Fis1). We show that protein levels of Bcl-2 and ERK were reduced in the MPP+-treated group compared with the control group. This effect was observed to be reversed upon treatment with 2,4-thiazolidinedione, as Bcl-2 and ERK expression levels were increased. We also observed that levels of the apoptotic protein Bax showed opposite changes compared to Bcl-2 and ERK levels. The results from this study confirm that pioglitazone/2,4-thiazolidinedione is able to activate PGC-1α and prevent damage of dopaminergic neurons and restore mitochondria ultrastructure through the regulation of mitochondria function.

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Cordycepin Improved Neuronal Synaptic Plasticity Through CREB-Induced NGF Up-Regulation Driven By Microglial M2 Polarization: A Symphony Communication Between Microglia and Neurons in AD

10.21203/rs.3.rs-184003/v1 ◽

2021 ◽

Author(s):

Linchi Jiao ◽

Mingyan Liu ◽

Xin Zhong ◽

Weifan Yao ◽

Guowei Ma ◽

...

Keyword(s):

Synaptic Plasticity ◽

Animal Behavior ◽

Cell Biology ◽

Neuronal Apoptosis ◽

Microglial Activation ◽

Neuroprotective Effect ◽

M2 Polarization ◽

Improved Learning

Abstract Background: The purpose of this study was to explore the molecular mechanism of the neuroprotective effect of Cordycepin (CCS) on improving the neuro-immune microenvironment of AD neurons by mediating microglial M2 polarization. Methods: We investigated microglial M2 polarization from M1, neuronal senescence, and synaptic plasticity by biological techniques such as animal behavior, cell biology, morphology, and bioinformatics. Results: CCS improved learning and memory impairment in 9-month-old APP/PS1 mice. CCS induced the microglial M2 polarization, up-regulated the expression and secretion level of NGF, and inhibited neuronal apoptosis, senescence, and synaptic damage caused by abnormal microglial activation in vivo and in vitro. CREB was activated by the M2 polarization and mediated the NGF expression and secretion after CCS treatment. CREB bound with the Sg3 promoter region of NGF (-1018~-1011), which increased NGF expression and secretion. CREB-induced NGF upregulation driven by microglial M2 polarization to improve the neuronal synaptic plasticity inhibits neuronal apoptosis and senescence. As a novel participant in the intercellular communication between MG and neurons, NGF contributed to the neuroprotective efficacy of CCS treatment. Conclusions: CCS improved the neuronal synaptic plasticity and senescence by promoting microglial M2 activation driven by CERB-induced NGF upregulation and conducted the symphony communication of MG-Neuron in AD.

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P7C3 Inhibits LPS-Induced Microglial Activation to Protect Dopaminergic Neurons Against Inflammatory Factor-Induced Cell Death in vitro and in vivo

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2018.00400 ◽

2018 ◽

Vol 12 ◽

Cited By ~ 5

Author(s):

Chao Gu ◽

Qingsong Hu ◽

Jiayuan Wu ◽

Chenchen Mu ◽

Haigang Ren ◽

...

Keyword(s):

Cell Death ◽

Dopaminergic Neurons ◽

Microglial Activation ◽

Inflammatory Factor

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Salsolinol—neurotoxic or Neuroprotective?

Neurotoxicity Research ◽

10.1007/s12640-019-00118-7 ◽

2019 ◽

Vol 37 (2) ◽

pp. 286-297 ◽

Cited By ~ 1

Author(s):

Magdalena Kurnik-Łucka ◽

Gniewomir Latacz ◽

Adrian Martyniak ◽

Andrzej Bugajski ◽

Katarzyna Kieć-Kononowicz ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Neuroprotective Effect ◽

Serum Levels ◽

In Vivo Experiments ◽

Pathophysiological Role ◽

The Central Nervous System ◽

Significant Release ◽

6 Hydroxydopamine

AbstractSalsolinol (6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline), widely available in many edibles, is considered to alter the function of dopaminergic neurons in the central nervous system and thus, multiple hypotheses on its either physiological and/or pathophysiological role have emerged. The aim of our work was to revisit its potentially neurotoxic and/or neuroprotective role through a series of both in vitro and in vivo experiments. Salsolinol in the concentration range 10–250 μM did not show any significant release of lactate dehydrogenase from necrotic SH-SY5Y cells and was able in the concentration of 50 and 100 μM to rescue SH-SY5Y cells from death induced by H2O2. Its neuroprotective effect against neurotoxin 6-hydroxydopamine was also determined. Salsolinol was found to decrease significantly the reactive oxygen species level in SH-SY5Y cells treated by 500 μM H2O2 and the caspase activity induced by 300 μM of H2O2 or 100 μM of 6-hydroxydopamine. Serum levels of TNFα and CRP of salsolinol-treated rats were not significantly different from control animals. Both TNFα and CRP served as indirect markers of neurotoxicity and/or neuroprotection. Although the neurotoxic properties of salsolinol have numerously been emphasized, its neuroprotective properties should not be neglected and need greater consideration.

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