Miriam Ulloa, Fernando Macías, Carmen Clapp, Gonzalo Martínez de la Escalera, Edith Arnold
{"title":"催乳素是星形胶质细胞中的内源性抗氧化因子,可通过 STAT3/NRF2 信号通路限制氧化应激诱导的星形胶质细胞死亡","authors":"Miriam Ulloa, Fernando Macías, Carmen Clapp, Gonzalo Martínez de la Escalera, Edith Arnold","doi":"10.1007/s11064-024-04147-3","DOIUrl":null,"url":null,"abstract":"<p><p>Oxidative stress-induced death of neurons and astrocytes contributes to the pathogenesis of numerous neurodegenerative diseases. While significant progress has been made in identifying neuroprotective molecules against neuronal oxidative damage, little is known about their counterparts for astrocytes. Prolactin (PRL), a hormone known to stimulate astroglial proliferation, viability, and cytokine expression, exhibits antioxidant effects in neurons. However, its role in protecting astrocytes from oxidative stress remains unexplored. Here, we investigated the effect of PRL against hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced oxidative insult in primary cortical astrocyte cultures. Incubation of astrocytes with PRL led to increased enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX), resulting in higher total antioxidant capacity. Concomitantly, PRL prevented H<sub>2</sub>O<sub>2</sub>-induced cell death, reactive oxygen species accumulation, and protein and lipid oxidation. The protective effect of PRL upon H<sub>2</sub>O<sub>2</sub>-induced cell death can be explained by the activation of both signal transducer and activator of transcription 3 (STAT3) and NFE2 like bZIP transcription factor 2 (NRF2) transduction cascades. We demonstrated that PRL induced nuclear translocation and transcriptional upregulation of Nrf2, concurrently with the transcriptional upregulation of the NRF2-dependent genes heme oxygenase 1, Sod1, Sod2, and Gpx1. Pharmacological blockade of STAT3 suppressed PRL-induced transcriptional upregulation of Nrf2, Sod1 and Gpx1 mRNA, and SOD and GPX activities. Furthermore, genetic ablation of the PRL receptor increased astroglial susceptibility to H<sub>2</sub>O<sub>2</sub>-induced cell death and superoxide accumulation, while diminishing their intrinsic antioxidant capacity. Overall, these findings unveil PRL as a potent antioxidant hormone that protects astrocytes from oxidative insult, which may contribute to brain neuroprotection.</p>","PeriodicalId":719,"journal":{"name":"Neurochemical Research","volume":null,"pages":null},"PeriodicalIF":3.7000,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11144156/pdf/","citationCount":"0","resultStr":"{\"title\":\"Prolactin is an Endogenous Antioxidant Factor in Astrocytes That Limits Oxidative Stress-Induced Astrocytic Cell Death via the STAT3/NRF2 Signaling Pathway.\",\"authors\":\"Miriam Ulloa, Fernando Macías, Carmen Clapp, Gonzalo Martínez de la Escalera, Edith Arnold\",\"doi\":\"10.1007/s11064-024-04147-3\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Oxidative stress-induced death of neurons and astrocytes contributes to the pathogenesis of numerous neurodegenerative diseases. While significant progress has been made in identifying neuroprotective molecules against neuronal oxidative damage, little is known about their counterparts for astrocytes. Prolactin (PRL), a hormone known to stimulate astroglial proliferation, viability, and cytokine expression, exhibits antioxidant effects in neurons. However, its role in protecting astrocytes from oxidative stress remains unexplored. Here, we investigated the effect of PRL against hydrogen peroxide (H<sub>2</sub>O<sub>2</sub>)-induced oxidative insult in primary cortical astrocyte cultures. Incubation of astrocytes with PRL led to increased enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX), resulting in higher total antioxidant capacity. Concomitantly, PRL prevented H<sub>2</sub>O<sub>2</sub>-induced cell death, reactive oxygen species accumulation, and protein and lipid oxidation. The protective effect of PRL upon H<sub>2</sub>O<sub>2</sub>-induced cell death can be explained by the activation of both signal transducer and activator of transcription 3 (STAT3) and NFE2 like bZIP transcription factor 2 (NRF2) transduction cascades. We demonstrated that PRL induced nuclear translocation and transcriptional upregulation of Nrf2, concurrently with the transcriptional upregulation of the NRF2-dependent genes heme oxygenase 1, Sod1, Sod2, and Gpx1. Pharmacological blockade of STAT3 suppressed PRL-induced transcriptional upregulation of Nrf2, Sod1 and Gpx1 mRNA, and SOD and GPX activities. Furthermore, genetic ablation of the PRL receptor increased astroglial susceptibility to H<sub>2</sub>O<sub>2</sub>-induced cell death and superoxide accumulation, while diminishing their intrinsic antioxidant capacity. 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引用次数: 0
摘要
氧化应激引起的神经元和星形胶质细胞死亡是多种神经退行性疾病的发病机制之一。尽管在确定神经元氧化损伤的神经保护分子方面取得了重大进展,但人们对星形胶质细胞的相应分子却知之甚少。催乳素(PRL)是一种已知能刺激星形胶质细胞增殖、活力和细胞因子表达的激素,在神经元中具有抗氧化作用。然而,它在保护星形胶质细胞免受氧化应激方面的作用仍有待探索。在这里,我们研究了 PRL 对原代皮质星形胶质细胞培养物中过氧化氢(H2O2)诱导的氧化损伤的影响。用 PRL 培养星形胶质细胞可提高超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GPX)的酶活性,从而提高总抗氧化能力。同时,PRL 还能防止 H2O2 诱导的细胞死亡、活性氧积累以及蛋白质和脂质氧化。PRL对H2O2诱导的细胞死亡的保护作用可通过激活信号转导子和转录激活子3(STAT3)以及类似于bZIP转录因子2(NRF2)的NFE2转导级联来解释。我们证实,PRL诱导Nrf2的核转位和转录上调,同时NRF2依赖基因血红素加氧酶1、Sod1、Sod2和Gpx1也转录上调。药物阻断 STAT3 可抑制 PRL 诱导的 Nrf2、Sod1 和 Gpx1 mRNA 转录上调以及 SOD 和 GPX 活性。此外,PRL 受体的遗传消减增加了星形胶质细胞对 H2O2 诱导的细胞死亡和超氧化物积累的敏感性,同时降低了其内在的抗氧化能力。总之,这些研究结果揭示了 PRL 是一种有效的抗氧化激素,它能保护星形胶质细胞免受氧化损伤,这可能有助于脑神经保护。
Prolactin is an Endogenous Antioxidant Factor in Astrocytes That Limits Oxidative Stress-Induced Astrocytic Cell Death via the STAT3/NRF2 Signaling Pathway.
Oxidative stress-induced death of neurons and astrocytes contributes to the pathogenesis of numerous neurodegenerative diseases. While significant progress has been made in identifying neuroprotective molecules against neuronal oxidative damage, little is known about their counterparts for astrocytes. Prolactin (PRL), a hormone known to stimulate astroglial proliferation, viability, and cytokine expression, exhibits antioxidant effects in neurons. However, its role in protecting astrocytes from oxidative stress remains unexplored. Here, we investigated the effect of PRL against hydrogen peroxide (H2O2)-induced oxidative insult in primary cortical astrocyte cultures. Incubation of astrocytes with PRL led to increased enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GPX), resulting in higher total antioxidant capacity. Concomitantly, PRL prevented H2O2-induced cell death, reactive oxygen species accumulation, and protein and lipid oxidation. The protective effect of PRL upon H2O2-induced cell death can be explained by the activation of both signal transducer and activator of transcription 3 (STAT3) and NFE2 like bZIP transcription factor 2 (NRF2) transduction cascades. We demonstrated that PRL induced nuclear translocation and transcriptional upregulation of Nrf2, concurrently with the transcriptional upregulation of the NRF2-dependent genes heme oxygenase 1, Sod1, Sod2, and Gpx1. Pharmacological blockade of STAT3 suppressed PRL-induced transcriptional upregulation of Nrf2, Sod1 and Gpx1 mRNA, and SOD and GPX activities. Furthermore, genetic ablation of the PRL receptor increased astroglial susceptibility to H2O2-induced cell death and superoxide accumulation, while diminishing their intrinsic antioxidant capacity. Overall, these findings unveil PRL as a potent antioxidant hormone that protects astrocytes from oxidative insult, which may contribute to brain neuroprotection.
期刊介绍:
Neurochemical Research is devoted to the rapid publication of studies that use neurochemical methodology in research on nervous system structure and function. The journal publishes original reports of experimental and clinical research results, perceptive reviews of significant problem areas in the neurosciences, brief comments of a methodological or interpretive nature, and research summaries conducted by leading scientists whose works are not readily available in English.