Related Experiment Video
Updated: Jun 1, 2025
Exploring the Two Herb Combination Strategy to Treat Injured PC12 Cells
Published on: November 18, 2022
Dichloroacetate protects against sulfur mustard-induced neurotoxicity via the PDK/PDH axis and Akt/Nrf2 pathway
Shanshan Zhang1, Yin Gong2, Jinfeng Cen1
1Faculty of Naval Medicine, Naval Medical University, Shanghai, 200433, China.
Abstract:
Sulfur mustard (SM) is a major toxic chemical threat to public health. Mitochondrial dysfunction is considered a critical contributing factor to mustard agent-induced damage. The brain is vulnerable to SM, which can lead to various types of acute and long-term psychiatric distress after exposure, but the neurotoxic mechanisms of SM, let alone drug candidates for antidotes, are seldom studied. In this study, we employed a library of mitochondrion-targeted compounds to screen for antidotes for SM-induced neurotoxicity. Our data revealed that dichloroacetate (DCA) noticeably reduced neuronal death and helped maintain the normal morphology and function of mitochondria both in vitro and in vivo. Further experiments revealed that DCA protected neurons by inhibiting pyruvate dehydrogenase kinase (PDK), thus upregulating pyruvate dehydrogenase (PDH) and activating the protein kinase B (Akt)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Overall, our results indicated that DCA could protect against SM-induced neurotoxicity through the PDK/PDH axis and the Akt/Nrf2 pathway, suggesting that DCA is a potentially novel antidote for SM poisoning.
Insights
Dichloroacetate (DCA) shows promise as an antidote for sulfur mustard (SM) neurotoxicity. It protects neurons by targeting mitochondrial dysfunction via the PDK/PDH axis and Akt/Nrf2 pathway.
Area of Science:
- Toxicology
- Neuroscience
- Mitochondrial Biology
Background:
- Sulfur mustard (SM) poses a significant public health risk, causing neurotoxicity and psychiatric distress.
- Mitochondrial dysfunction is a key mechanism in SM-induced cellular damage.
- Neurotoxic mechanisms of SM and potential antidotes remain underexplored.
Purpose of the Study:
- To screen mitochondrion-targeted compounds for antidotes against SM-induced neurotoxicity.
- To investigate the protective effects of dichloroacetate (DCA) against SM neurotoxicity.
Main Methods:
- Screening of mitochondrion-targeted compounds.
- In vitro and in vivo experiments to assess neuronal survival and mitochondrial function.
- Molecular analysis of the pyruvate dehydrogenase kinase (PDK)/pyruvate dehydrogenase (PDH) axis and the Akt/Nrf2 pathway.
Main Results:
- Dichloroacetate (DCA) significantly reduced neuronal death caused by SM exposure.
- DCA maintained normal mitochondrial morphology and function in neurons.
- DCA functions by inhibiting PDK, upregulating PDH, and activating the Akt/Nrf2 pathway.
Conclusions:
- DCA demonstrates neuroprotective effects against sulfur mustard toxicity.
- The protective mechanism involves the PDK/PDH axis and the Akt/Nrf2 signaling pathway.
- DCA is a potential novel antidote for SM poisoning.
Related Concept Videos
01:24Acetals and Thioacetals as Protecting Groups for Aldehydes and Ketones
In the presence of multiple functional groups, when selective reduction of one group over the other is desired, groups like aldehydes and ketones that form acetals...
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...