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Published on: January 22, 2016
Endoplasmic Reticulum Stress Mediates Methamphetamine-Induced Blood-Brain Barrier Damage
Xiaojuan Qie1,2, Di Wen1, Hongyan Guo1
1Hebei Key Laboratory of Forensic Medicine, Department of Forensic Medicine, Hebei Medical UniversityShijiazhuang, China.
Abstract:
Methamphetamine (METH) abuse causes serious health problems worldwide, and long-term use of METH disrupts the blood-brain barrier (BBB). Herein, we explored the potential mechanism of endoplasmic reticulum (ER) stress in METH-induced BBB endothelial cell damage in vitro and the therapeutic potential of endoplasmic reticulum stress inhibitors for METH-induced BBB disruption in C57BL/6J mice. Exposure of immortalized BMVEC (bEnd.3) cells to METH significantly decreased cell viability, induced apoptosis, and diminished the tightness of cell monolayers. METH activated ER stress sensor proteins, including PERK, ATF6, and IRE1, and upregulated the pro-apoptotic protein CHOP. The ER stress inhibitors significantly blocked the upregulation of CHOP. Knockdown of CHOP protected bEnd.3 cells from METH-induced cytotoxicity. Furthermore, METH elevated the production of reactive oxygen species (ROS) and induced the dysfunction of mitochondrial characterized by a Bcl2/Bax ratio decrease, mitochondrial membrane potential collapse, and cytochrome c. ER stress release was partially reversed by ROS inhibition, and cytochrome c release was partially blocked by knockdown of CHOP. Finally, PBA significantly attenuated METH-induced sodium fluorescein (NaFluo) and Evans Blue leakage, as well as tight junction protein loss, in C57BL/6J mice. These data suggest that BBB endothelial cell damage was caused by METH-induced endoplasmic reticulum stress, which further induced mitochondrial dysfunction, and that PBA was an effective treatment for METH-induced BBB disruption.
Insights
Methamphetamine disrupts the blood-brain barrier (BBB) by inducing endoplasmic reticulum (ER) stress and mitochondrial dysfunction in brain endothelial cells. ER stress inhibitors show therapeutic potential for treating METH-induced BBB damage.
Area of Science:
- Neuroscience
- Cell Biology
- Toxicology
Background:
- Methamphetamine (METH) abuse is a global health issue with severe consequences.
- Long-term METH use is known to disrupt the blood-brain barrier (BBB), a critical protective interface.
- The precise mechanisms underlying METH-induced BBB damage require further elucidation.
Purpose of the Study:
- To investigate the role of endoplasmic reticulum (ER) stress in METH-induced damage to BBB endothelial cells.
- To explore the therapeutic efficacy of ER stress inhibitors in mitigating METH-induced BBB disruption.
- To elucidate the molecular pathways linking METH exposure, ER stress, and BBB integrity.
Main Methods:
- Utilized immortalized brain microvascular endothelial cells (bEnd.3) for in vitro studies.
- Assessed cell viability, apoptosis, and monolayer integrity following METH exposure.
- Investigated the activation of ER stress markers (PERK, ATF6, IRE1, CHOP) and mitochondrial dysfunction.
- Employed ER stress inhibitors and CHOP knockdown as therapeutic interventions.
- Validated findings in a C57BL/6J mouse model using sodium fluorescein and Evans Blue leakage assays.
Main Results:
- METH exposure decreased bEnd.3 cell viability, induced apoptosis, and compromised BBB tightness.
- METH activated key ER stress pathways and upregulated the pro-apoptotic protein CHOP.
- Inhibition of ER stress and knockdown of CHOP protected cells from METH-induced cytotoxicity.
- METH elevated reactive oxygen species (ROS) production and induced mitochondrial dysfunction.
- PBA treatment significantly reduced METH-induced BBB leakage and tight junction protein loss in mice.
Conclusions:
- METH-induced BBB endothelial cell damage is mediated by endoplasmic reticulum stress, leading to mitochondrial dysfunction.
- Targeting ER stress, particularly CHOP, offers a promising therapeutic strategy for METH-induced BBB disruption.
- PBA demonstrates significant potential as an effective treatment for mitigating METH-induced BBB damage.
