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Astragaloside IV inhibits astrocyte senescence: implication in Parkinson’s disease
Journal of Neuroinflammation ( IF 9.3 ) Pub Date : 2020-04-06 , DOI: 10.1186/s12974-020-01791-8
Mei-Ling Xia , Xia-Hong Xie , Jian-Hua Ding , Ren-Hong Du , Gang Hu

Senescent astrocytes have been implicated in the aging brain and neurodegenerative disorders, including Parkinson’s disease (PD). Astragaloside IV (AS-IV) is an antioxidant derivative from a traditional Chinese herbal medicine Astragalus membraneaceus Bunge and exerts anti-inflammatory and longevity effects and neuroprotective activities. However, its effect on astrocyte senescence in PD remains to be defined. Long culture-induced replicative senescence model and lipopolysaccharide/1-methyl-4-phenylpyridinium (LPS/MPP+)-induced premature senescence model and a mouse model of PD were used to investigate the effect of AS-IV on astrocyte senescence in vivo and in vitro. Immunocytochemistry, qPCR, subcellular fractionation, flow cytometric analyses, and immunohistochemistry were subsequently conducted to determine the effects of AS-IV on senescence markers. We found that AS-IV inhibited the astrocyte replicative senescence and LPS/MPP+-induced premature senescence, evidenced by decreased senescence-associated β-galactosidase activity and expression of senescence marker p16, and increased nuclear level of lamin B1, and reduced pro-inflammatory senescence-associated secretory phenotype. More importantly, we showed that AS-IV protected against the loss of dopamine neurons and behavioral deficits in the mouse model of PD, which companied by reduced accumulation of senescent astrocytes in substantia nigra compacta. Mechanistically, AS-IV promoted mitophagy, which reduced damaged mitochondria accumulation and mitochondrial reactive oxygen species generation and then contributed to the suppression of astrocyte senescence. The inhibition of autophagy abolished the suppressive effects of AS-IV on astrocyte senescence. Our findings reveal that AS-IV prevents dopaminergic neurodegeneration in PD via inhibition of astrocyte senescence through promoting mitophagy and suggest that AS-IV is a promising therapeutic strategy for the treatment of age-associated neurodegenerative diseases such as PD.

中文翻译:

黄芪甲苷IV抑制星形胶质细胞衰老:对帕金森氏病的影响

衰老的星形胶质细胞与大脑老化和神经退行性疾病有关,包括帕金森氏病(PD)。黄芪甲苷IV(AS-IV)是一种中草药黄芪膜抗氧化剂的抗氧化剂衍生物,具有抗炎和延年益寿的作用以及神经保护活性。然而,其对PD中星形胶质细胞衰老的影响尚待确定。长培养诱导的复制衰老模型和脂多糖/ 1-甲基-4-苯基吡啶(LPS / MPP +)诱导的早衰模型和PD的小鼠模型用于研究AS-IV在体内和体外对星形胶质细胞衰老的影响。体外。免疫细胞化学,qPCR,亚细胞分级分离,流式细胞仪分析,随后进行免疫组织化学测定AS-IV对衰老标记的影响。我们发现AS-IV抑制星形胶质细胞复制性衰老和LPS / MPP +诱导的过早衰老,这可由衰老相关的β-半乳糖苷酶活性和衰老标志物p16的表达降低,以及核纤层蛋白B1的核水平升高和促炎性降低来证明衰老相关的分泌表型。更重要的是,我们显示AS-IV可以防止多巴胺神经元的丢失和PD小鼠模型中的行为缺陷,这与黑质致密部中衰老的星形胶质细胞的蓄积相伴。从机理上讲,AS-IV促进了线粒体吞噬,减少受损的线粒体积累和线粒体活性氧的产生,然后有助于抑制星形胶质细胞的衰老。自噬的抑制消除了AS-IV对星形胶质细胞衰老的抑制作用。我们的发现表明,AS-IV通过促进线粒体吞噬抑制星形胶质细胞衰老,从而防止PD中的多巴胺能神经变性,并表明AS-IV是治疗与年龄相关的神经退行性疾病(如PD)的一种有前途的治疗策略。
更新日期:2020-04-22
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