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Updated: Oct 15, 2025
Experimental Models to Study the Neuroprotection of Acidic Postconditioning Against Cerebral Ischemia
Published on: July 31, 2017
DCA Protects against Oxidation Injury Attributed to Cerebral Ischemia-Reperfusion by Regulating Glycolysis through
Xiaoyong Zhao1,2, Shan Li1, Yunchang Mo1
1Department of Anesthesiology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province, China.
Abstract:
Cerebral ischemic stroke (IS) is still a difficult problem to be solved; energy metabolism failure is one of the main factors causing mitochondrion dysfunction and oxidation stress damage within the pathogenesis of cerebral ischemia, which produces considerable reactive oxygen species (ROS) and opens the blood-brain barrier. Dichloroacetic acid (DCA) can inhibit pyruvate dehydrogenase kinase (PDK). Moreover, DCA has been indicated with the capability of increasing mitochondrial pyruvate uptake and promoting oxidation of glucose in the course of glycolysis, thereby improving the activity of pyruvate dehydrogenase (PDH). As a result, pyruvate flow is promoted into the tricarboxylic acid cycle to expedite ATP production. DCA has a protective effect on IS and brain ischemia/reperfusion (I/R) injury, but the specific mechanism remains unclear. This study adopted a transient middle cerebral artery occlusion (MCAO) mouse model for simulating IS and I/R injury in mice. We investigated the mechanism by which DCA regulates glycolysis and protects the oxidative damage induced by I/R injury through the PDK2-PDH-Nrf2 axis. As indicated from the results of this study, DCA may improve glycolysis, reduce oxidative stress and neuronal death, damage the blood-brain barrier, and promote the recovery of oxidative metabolism through inhibiting PDK2 and activating PDH. Additionally, DCA noticeably elevated the neurological score and reduced the infarct volume, brain water content, and necrotic neurons. Moreover, as suggested from the results, DCA elevated the content of Nrf2 as well as HO-1, i.e., the downstream antioxidant proteins pertaining to Nrf2, while decreasing the damage of BBB and the degradation of tight junction proteins. To simulate the condition of hypoxia and ischemia in vitro, HBMEC cells received exposure to transient oxygen and glucose deprivation (OGD). The DCA treatment is capable of reducing the oxidative stress and blood-brain barrier of HBMEC cells after in vitro hypoxia and reperfusion (H/R). Furthermore, this study evidenced that HBMEC cells could exhibit higher susceptibility to H/R-induced oxidative stress after ML385 application, the specific inhibitor of Nrf2. Besides, the protection mediated by DCA disappeared after ML385 application. To sum up, as revealed from the mentioned results, DCA could exert the neuroprotective effect on oxidative stress and blood-brain barrier after brain I/R injury via PDK2-PDH-Nrf2 pathway activation. Accordingly, the PDK2-PDH-Nrf2 pathway may play a key role and provide a new pharmacology target in cerebral IS and I/R protection by DCA.
Insights
Dichloroacetic acid (DCA) protects against cerebral ischemic stroke by improving glycolysis and reducing oxidative stress via the PDK2-PDH-Nrf2 pathway. This mechanism enhances ATP production and neuronal survival, offering a new therapeutic target for stroke.
Area of Science:
- Neuroscience and Neuroprotection
- Metabolic pathways in ischemia
- Oxidative stress mechanisms
Background:
- Cerebral ischemic stroke (IS) involves energy metabolism failure, mitochondrial dysfunction, and oxidative stress, leading to blood-brain barrier (BBB) damage.
- Dichloroacetic acid (DCA) is known to inhibit pyruvate dehydrogenase kinase (PDK) and enhance pyruvate dehydrogenase (PDH) activity, potentially improving cellular energy production.
- The precise neuroprotective mechanisms of DCA in IS and ischemia/reperfusion (I/R) injury remain incompletely understood.
Purpose of the Study:
- To investigate the mechanism by which DCA regulates glycolysis and protects against oxidative damage in cerebral I/R injury.
- To elucidate the role of the PDK2-PDH-Nrf2 axis in DCA's neuroprotective effects.
- To evaluate DCA's impact on neurological scores, infarct volume, and BBB integrity in a mouse model of IS.
Main Methods:
- A transient middle cerebral artery occlusion (MCAO) mouse model was used to simulate IS and I/R injury.
- In vitro experiments utilized human brain microvascular endothelial (HBMEC) cells subjected to oxygen and glucose deprivation (OGD) to mimic hypoxia and ischemia.
- The study assessed DCA's effects on glycolysis, oxidative stress markers, Nrf2 activation, BBB integrity, and tight junction proteins, using ML385 (an Nrf2 inhibitor) to confirm pathway involvement.
Main Results:
- DCA treatment improved glycolysis, reduced oxidative stress and neuronal death, preserved BBB integrity, and promoted oxidative metabolism recovery by inhibiting PDK2 and activating PDH.
- Mice treated with DCA showed significantly improved neurological scores, reduced infarct volume, brain water content, and necrotic neurons.
- DCA elevated Nrf2 and its downstream antioxidant HO-1, while decreasing BBB damage and tight junction protein degradation; these protective effects were abolished by ML385.
Conclusions:
- DCA exerts neuroprotection against oxidative stress and BBB damage in cerebral I/R injury by activating the PDK2-PDH-Nrf2 pathway.
- Inhibition of PDK2 and activation of PDH by DCA are crucial for improving glycolysis and enhancing the antioxidant response via Nrf2.
- The PDK2-PDH-Nrf2 pathway represents a key therapeutic target for DCA-mediated protection in cerebral IS and I/R injury.
