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Malate-aspartate shuttle inhibitor aminooxyacetic acid blocks lipopolysaccharides-induced activation of BV2 microglia
Wangsong Shang1, Xunbin Wei1, Weihai Ying1,2,3
1Med-X Research Institute and School of Biomedical Engineering, Shanghai Jiao Tong UniversityShanghai, China.
Abstract:
NADH shuttles, including malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, mediate the transfer of the reducing equivalents of cytosolic NADH into mitochondria. In our current study, we used BV2 microglia as a cellular model to determine the roles of NADH shuttles in lipopolysaccharides (LPS)-induced microglial activation. We found that aminooxyacetic acid (AOAA), a widely used MAS inhibitor, significantly attenuated LPS-induced increases in the levels of nitric oxide-a hallmarker of microglial activation. Our Western Blot assays also showed that AOAA blocked the LPS-induced increases in the protein levels of iNOS, TNF-α and COX-2. Furthermore, we found that AOAA decreased LPS-induced nuclear translocation of NF-κB. Collectively, our study has suggested that AOAA may be a new agent for inhibiting microglial activation. Our study has also suggested that MAS may be a novel target for modulating microglial activation under pathological conditions.
Insights
Aminooxyacetic acid (AOAA), an inhibitor of the malate-aspartate shuttle (MAS), reduces microglial activation markers like nitric oxide. This suggests MAS inhibition is a potential therapeutic strategy for neuroinflammation.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- NADH shuttles, such as the malate-aspartate shuttle (MAS) and glycerol-3-phosphate shuttle, are crucial for transferring reducing equivalents from cytosolic NADH into mitochondria.
- Microglial activation, often triggered by lipopolysaccharides (LPS), is a key process in neuroinflammation and is associated with the production of nitric oxide.
- Understanding the role of NADH shuttles in microglial activation is essential for developing targeted therapeutic interventions.
Purpose of the Study:
- To investigate the role of NADH shuttles in lipopolysaccharide (LPS)-induced microglial activation using BV2 microglia as a cellular model.
- To determine if inhibiting the malate-aspartate shuttle (MAS) can modulate LPS-induced microglial responses.
- To explore aminooxyacetic acid (AOAA) as a potential agent for controlling microglial activation.
Main Methods:
- Utilized BV2 microglia as a cellular model to study microglial activation.
- Administered lipopolysaccharides (LPS) to induce microglial activation.
- Employed aminooxyacetic acid (AOAA), a malate-aspartate shuttle (MAS) inhibitor, to assess its effects.
- Measured nitric oxide levels as a marker of microglial activation.
- Performed Western Blot assays to quantify protein levels of iNOS, TNF-α, and COX-2.
- Assessed the nuclear translocation of NF-κB.
Main Results:
- Aminooxyacetic acid (AOAA) significantly attenuated LPS-induced increases in nitric oxide levels.
- AOAA effectively blocked the LPS-induced upregulation of iNOS, TNF-α, and COX-2 protein expression.
- AOAA treatment reduced the LPS-induced nuclear translocation of NF-κB.
- These findings indicate that inhibiting the malate-aspartate shuttle impacts key inflammatory pathways in microglia.
Conclusions:
- The malate-aspartate shuttle (MAS) plays a significant role in LPS-induced microglial activation.
- Aminooxyacetic acid (AOAA), by inhibiting MAS, demonstrates potential as a therapeutic agent to suppress microglial activation.
- Targeting the malate-aspartate shuttle presents a novel strategy for modulating neuroinflammation in pathological conditions.
