Astragaloside IV ameliorates motor deficits and dopaminergic neuron degeneration via inhibiting neuroinflammation and oxidative stress in a Parkinson's disease mouse model

Yang, Cong; Mo, Yousheng; Xu, Erjin; Wen, Huihong; Wei, Renrong; Li, Shaoling; Zheng, Jiayi; Li, Weirong; Le, Baoluu; Chen, Yonggen; Pan, Huafeng; Huang, Suli; Wang, Shengqiang; Wang, Qi

doi:10.1016/j.intimp.2019.05.036

Cited by 78 publications

(45 citation statements)

References 41 publications

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“…Similar effects were found in an Aβ1-42-induced AD mouse model treated with an A. oxyphylla-Schisandra chinensis herbal formulation and an LPS-induced AD mouse model treated with Nootkatone derived from A. oxyphylla [29,31]. Furthermore, in addition to the inhibition of the NF-κB signaling pathway, astragaloside IV isolated from A. membranaceus showed anti-inflammatory and antioxidant properties in the MPTP-induced PD mouse model through the activation of the Nrf2 pathway [57]. The Nrf2 pathway inhibits activation of the NF-κB pathway by reducing ROS and preventing IκBα degradation, whereas the NF-κB pathway antagonizes the Nrf2 pathway by competing for the binding domain of the Nrf2-antioxidant response element [83,84].…”

Section: Regulation Of Immunomodulation and Neuroinflammationsupporting

confidence: 64%

Traditional Chinese medicine-based neurorestorative therapy for Alzheimer’s and Parkinson’s disease

Zhu¹,

Zhang²,

Lui³

et al. 2019

Journal of Neurorestoratology

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The prevalence of multiple neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), has been dramatically increasing, particularly in the aging population. However, the currently available therapies merely alleviate the symptoms of these diseases and are unable to retard disease progression significantly. Traditional Chinese medicine (TCM) has been used in clinical practice for thousands of years for ameliorating symptoms or interfering with the pathogenesis of aging- associated diseases. Modern pharmacological studies have proved that TCM imparts disease-modifying therapeutic effects against these diseases, such as protection of neurons, clearance of protein aggregates, and regulation of neuroinflammation. This review summarizes the evidence from recent studies on AD and PD therapies regarding the neuroprotective activities and molecular mechanisms of a series of TCM formulations comprising herbs and their active ingredients. The findings of this review support the use of TCM as an alternative source of therapy for the treatment of neurodegenerative diseases.

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Section: Regulation Of Immunomodulation and Neuroinflammationsupporting

confidence: 64%

Traditional Chinese medicine-based neurorestorative therapy for Alzheimer’s and Parkinson’s disease

Zhu¹,

Zhang²,

Lui³

et al. 2019

Journal of Neurorestoratology

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“…And celastrol treatment did not caused signi cant restoration of loss of dopaminergic neurons, impairment of motor function and the neuroin ammation in Nrf2-KO mice, revealing that Nrf2 mediates the neuroprotective effects of celastrol in PD. It's reported that Nrf2/HO-1 mediates the neuroprotective effect of mangiferin by attenuating mitochondria-related apoptosis and NLRP3 induced neuroin ammation; astragaloside IV ameliorates motor de cits and dopaminergic neuron degeneration via inhibiting NLRP3 mediated neuroin ammation and oxidative stress in PD mouse model [35]. Here, our ndings show that celastrol treatment protects against the loss of dopaminergic neurons via the mediation of Nrf2-NLRP3 axis in MPTP-induced PD mouse model.…”

Section: Discussionsupporting

confidence: 52%

“…Recently, it's reported that DDO7263, a novel Nrf2 activator targeting brain tissue, can protect against MPTP-induced PD model via inhibition of the NLRP3 in ammasome and oxidative stress [34]. Astragaloside IV can ameliorate motor de cits and the loss of dopaminergic neuron induced by MPTP through suppression of NLRP3 in ammasome [35]. Besides, previous studies have revealed that celastrol inhibits microglial pyroptosis and attenuates in ammatory reaction in acute spinal cord injury rats [36].…”

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confidence: 99%

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Zhang

Zhao

Wang

et al. 2020

Preprint

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Background: Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied by chronic neuroinflammation, oxidative stress, and widespread accumulation of α-synuclein. Celastrol (Cel), a potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged as a neuroprotective agent. However, the mechanisms by which celastrol is neuroprotective in PD has not yet been elucidated. Methods: The MPTP and AAV-mediated human wild-type α-syn overexpression within SNc induced PD mouse models were employed in this study. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO and Caspase1-KO), we identified that celastrol effectively inhibited the NLRP3 inflammasome activation, mitigated motor deficits and nigrostriatal dopaminergic degeneration through Nrf2-NLRP3-Caspase1 pathway. Results: Here we show that celastrol protected against the loss of dopaminergic neurons, mitigated the neuroinflammation and motor deficits in both MPTP-induced PD mouse model and AAV-mediated human α-syn overexpression PD model. Whole-genome deep sequencing analysis reveals that Nrf2, NLRP3 and Caspase1 in SNc may be associated with the neuroprotective actions of celastrol in PD. Conclusions: These findings suggest that Nrf2-NLRP3-Caspase1 axis may be a key target of celastrol in PD treatment, and highlight the favorable properties linked to neuroprotection of celastrol, making celastrol as a promising disease-modifying agent for PD.

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“…Pharmacological and clinical practice research has demonstrated that Astragalus displays a wide range of clinical effects, including immune regulation, cardiovascular protection, anti-inflammatory, hepatoprotective, antidiabetic, anticancer and neuroprotection (28,29). As one of the primary active ingredients of Astragalus, AS-IV is regarded as the factor for quality evaluation of Astragalus in the Chinese Pharmacopeia, and has been reported to display cardioprotective (30) and anti-inflammatory effects via regulation of the NF-κB and activator protein 1 signaling pathways (31).…”

Section: Discussionmentioning

confidence: 99%

Astragaloside IV attenuates hypoxia‑induced pulmonary vascular remodeling via the Notch signaling pathway

et al. 2020

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The Notch signaling pathway participates in pulmonary artery smooth muscle cell (PASMC) proliferation and apoptosis. Astragaloside IV (AS-IV) is an effective antiproliferative treatment for vascular diseases. The present study aimed to investigate the protective effects and mechanisms underlying AS-IV on hypoxia-induced PASMC proliferation and pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) model rats. Rats were divided into the following four groups: i) normoxia; ii) hypoxia (10% O 2); iii) treatment, hypoxia + intragastrical administration of AS-IV (2 mg/kg) daily for 28 days; and iv) DAPT, hypoxia + AS-IV treatment + subcutaneous administration of DAPT (10 mg/kg) three times daily. The effects of AS-IV treatment on the development of hypoxia-induced PAH, right ventricle (RV) hypertrophy and pulmonary vascular remodeling were examined. Furthermore, PASMCs were treated with 20 µmol/l AS-IV under hypoxic conditions for 48 h. To determine the effect of Notch signaling in vascular remodeling and the potential mechanisms underlying AS-IV treatment, 5 mmol/l γ-secretase inhibitor [N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT)] was used. Cell viability and apoptosis were determined by performing the MTT assay and flow cytometry, respectively. Immunohistochemistry was conducted to detect the expression of proliferating cell nuclear antigen (PCNA). Moreover, the mRNA and protein expression levels of Notch-3, Jagged-1, hes family bHLH transcription factor 5 (Hes-5) and PCNA were measured via reverse transcription-quantitative PCR and western blotting, respectively. Compared with the normoxic group, hypoxia-induced PAH model rats displayed characteristics of PAH and RV hypertrophy, whereas AS-IV treatment alleviated PAH and prevented RV hypertrophy. AS-IV also inhibited hypoxia-induced pulmonary vascular remodeling, as indicated by reduced wall thickness and increased lumen diameter of pulmonary arterioles, and decreased muscularization of distal pulmonary vasculature in hypoxia-induced PAH model rats. Compared with normoxia, hypoxia promoted PASMC proliferation in vitro, whereas AS-IV treatment inhibited hypoxia-induced PASMC proliferation by downregulating PCNA expression in vitro and in vivo. In hypoxia-treated PAH model rats and cultured PASMCs, AS-IV treatment reduced the expression levels of Jagged-1, Notch-3 and Hes-5. Furthermore, Notch signaling inhibition via DAPT significantly inhibited the pulmonary vascular remodeling effect of AS-IV in vitro and in vivo. Collectively, the results indicated that AS-IV effectively reversed hypoxia-induced pulmonary vascular remodeling and PASMC proliferation via the Notch signaling pathway. Therefore, the present study provided novel insights into the mechanism underlying the use of AS-IV for treatment of vascular diseases, such as PAH.

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Astragaloside IV ameliorates motor deficits and dopaminergic neuron degeneration via inhibiting neuroinflammation and oxidative stress in a Parkinson's disease mouse model

Cited by 78 publications

References 41 publications

Traditional Chinese medicine-based neurorestorative therapy for Alzheimer’s and Parkinson’s disease

Traditional Chinese medicine-based neurorestorative therapy for Alzheimer’s and Parkinson’s disease

The Nrf2-NLRP3-Caspase1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease

Astragaloside IV attenuates hypoxia‑induced pulmonary vascular remodeling via the Notch signaling pathway

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