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 astrocyte...

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Bibliographic Details
Published in:Neurochemical research 2024-07, Vol.49 (7), p.1879-1901
Main Authors: Ulloa, Miriam, Macías, Fernando, Clapp, Carmen, Martínez de la Escalera, Gonzalo, Arnold, Edith
Format: Article
Language:English
Subjects:
Ablation
Accumulation
Animals
Antioxidants
Antioxidants - pharmacology
Astrocytes
Astrocytes - drug effects
Astrocytes - metabolism
Biochemistry
Biomedical and Life Sciences
Biomedicine
Cell Biology
Cell death
Cell Death - drug effects
Cell Death - physiology
Cells, Cultured
Enzymatic activity
Glutathione
Glutathione peroxidase
Heme oxygenase (decyclizing)
Hydrogen peroxide
Hydrogen Peroxide - pharmacology
Hydrogen Peroxide - toxicity
Lipid peroxidation
Lipids
Mice
Mortality
Neurochemistry
Neurodegenerative diseases
Neurology
Neurons
Neuroprotection
Neurosciences
NF-E2-Related Factor 2 - metabolism
Nuclear transport
Original Paper
Oxidation
Oxidative stress
Oxidative Stress - drug effects
Oxidative Stress - physiology
Pathogenesis
Peroxidase
Prolactin
Prolactin - metabolism
Prolactin - pharmacology
Rats
Reactive oxygen species
Signal transduction
Signal Transduction - drug effects
Signal Transduction - physiology
Stat3 protein
STAT3 Transcription Factor - metabolism
Superoxide dismutase
Translocation
Up-regulation
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Summary: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 2 O 2 )-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 2 O 2 -induced cell death, reactive oxygen species accumulation, and protein and lipid oxidation. The protective effect of PRL upon H 2 O 2 -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 2 O 2 -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.
ISSN:0364-3190
1573-6903
1573-6903
DOI:10.1007/s11064-024-04147-3