Abstract
Transient cerebral ischemia (TCI) occurs when blood flow to the brain is ceased or dramatically reduced. TCI causes energy depletion and oxidative stress, which leads to neuronal death and cognitive impairment. Dichloroacetic acid (DCA) acts as an inhibitor of pyruvate dehydrogenase kinase (PDK). Additionally, DCA is known to increase mitochondrial pyruvate uptake and promotes glucose oxidation during glycolysis, thus enhancing pyruvate dehydrogenase (PDH) activity. In this study, we investigated whether the inhibition of PDK activity by DCA, which increases the rate of pyruvate conversion to adenosine triphosphate (ATP), prevents ischemia-induced neuronal death. We used a rat model of TCI, which was induced by common carotid artery occlusion and hypovolemia for 7 min while monitoring the electroencephalography for sustained isoelectric potential. Male Sprague-Dawley rats were given an intraperitoneal injection of DCA (100 mg/kg) with pyruvate (50 mg/kg) once per day for 2 days after insult. The vehicle, DCA only or pyruvate on rats was injected on the same schedule. Our study demonstrated that the combined administration of DCA with pyruvate significantly decreased neuronal death, oxidative stress, microglia activation when compared with DCA, or pyruvate injection alone. These findings suggest that the administration of DCA with pyruvate may enhance essential metabolic processes, which in turn promotes the regenerative capacity of the post-ischemic brain.
Highlights
Transient cerebral ischemia (TCI) is the most commonly developed neurological disorder after heart attack or thromboembolism
Dichloroacetic acid (DCA) has been demonstrated to increase the uptake of pyruvate into the mitochondria and improve the ratio of glucose oxidation during the glycolysis process, enhancing pyruvate dehydrogenase (PDH) activity [19, 20]. Based on these chemical characteristics, we investigated whether the inhibition of pyruvate dehydrogenase kinase (PDK) activity by DCA, which increases the rate of pyruvate converted to adenosine triphosphate (ATP), prevents neuronal damage after TCI
We found that DCA treatment with pyruvate reduced the number of FluoroJade B (FJB) positive neurons after TCI when compared to the vehicle-treated group
Summary
Transient cerebral ischemia (TCI) is the most commonly developed neurological disorder after heart attack or thromboembolism. The process of blood recirculation following the cessation of DCA Reduces Ischemic Neuronal Death blood flow may exacerbate certain aspects of brain injury, such as increased infarct volume and worsened clinical outcome after stroke. This phenomenon has been called “reperfusion injury” following ischemia [1]. Either oxygen or glucose-induced reperfusion injury after ischemia is accompanied by multiple cellular and molecular responses, such as the activation of microglia [5] and BBB disruption [6, 7] as well as the production of ROS [8,9,10]
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