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Morphine-induced modulation of Nrf2-antioxidant response element signaling pathway in primary human brain
Sandrine Reymond1,2, Tatjana Vujić1,2, Domitille Schvartz1,2
1Department of Medicine, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Abstract:
Morphine is one of the most potent opioid analgesic used for pain treatment. Morphine action in the central nervous system requires crossing the blood-brain barrier. Due to the controversial relationship between morphine and oxidative stress, the potential pro- or antioxidant effects of morphine in the blood-brain barrier is important to be understood, as oxidative stress could cause its disruption and predispose to neurodegenerative diseases. However, investigation is scarce in human brain endothelial cells. Therefore, the present study evaluated the impact of morphine exposure at three different concentrations (1, 10 and 100 µM) for 24 h and 48 h on primary human brain microvascular endothelial cells. A quantitative data-independent acquisition mass spectrometry strategy was used to analyze proteome modulations. Almost 3000 proteins were quantified of which 217 were reported to be significantly regulated in at least one condition versus untreated control. Pathway enrichment analysis unveiled dysregulation of the Nrf2 pathway involved in oxidative stress response. Seahorse assay underlined mitochondria dysfunctions, which were supported by significant expression modulations of relevant mitochondrial proteins. In conclusion, our study revealed the dysregulation of the Nrf2 pathway and mitochondria dysfunctions after morphine exposure, highlighting a potential redox imbalance in human brain endothelial cells.
Insights
Morphine exposure disrupts the Nrf2 pathway and impairs mitochondria in human brain endothelial cells, suggesting a potential redox imbalance. This finding is crucial for understanding morphine
Area of Science:
- Neuroscience
- Cell Biology
- Pharmacology
Background:
- Morphine, a potent opioid analgesic, must cross the blood-brain barrier for central nervous system effects.
- Oxidative stress is linked to blood-brain barrier disruption and neurodegenerative diseases.
- The effects of morphine on blood-brain barrier oxidative stress are not well understood, especially in human brain endothelial cells.
Purpose of the Study:
- To investigate the impact of morphine on primary human brain microvascular endothelial cells.
- To analyze proteomic alterations and cellular pathway dysregulations induced by morphine exposure.
- To assess potential redox imbalance and mitochondrial dysfunction in response to morphine.
Main Methods:
- Primary human brain microvascular endothelial cells were exposed to morphine (1, 10, 100 µM) for 24 and 48 hours.
- Quantitative data-independent acquisition mass spectrometry was employed for proteome analysis.
- Seahorse assay was utilized to evaluate mitochondrial function.
Main Results:
- Over 3000 proteins were quantified, with 217 significantly regulated under morphine treatment.
- Pathway enrichment analysis revealed dysregulation of the Nrf2 pathway, crucial for oxidative stress response.
- Mitochondrial dysfunction was indicated by Seahorse assays and modulated expression of mitochondrial proteins.
Conclusions:
- Morphine exposure leads to Nrf2 pathway dysregulation in human brain endothelial cells.
- Significant mitochondrial dysfunction occurs following morphine treatment.
- These findings suggest a potential redox imbalance in the blood-brain barrier endothelium.
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