Combined Treatment With Dichloroacetic Acid and Pyruvate Reduces Hippocampal Neuronal Death After Transient Cerebral Ischemia

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.

Sodium Dichloroacetate Stimulates Angiogenesis by Improving Endothelial Precursor Cell Function in an AKT/GSK-3β/Nrf2 Dependent Pathway in Vascular Dementia Rats

“…Previous studies have shown that DCA plays an essential role in vascular protection and in promoting revascularization of blood vessels (Deuse et al, 2014; Hong et al, 2018) and improves vascular calcification in patients with atherosclerosis (Yang Y. et al, 2018). DCA might also have therapeutic effects in the context of vascular-related diseases.…”

“…Recent studies had found that DCA acts as a potential vasoprotective agent by inhibiting PDK2 and reducing coronary endarterium proliferation (Deuse et al, 2014). Further, DCA promotes brain regeneration after cerebral ischemia (Hong et al, 2018), which indicates that DCA might play an important role in VD.…”

Transient Receptor Potential Melastatin 2 (TRPM2) Inhibition by Antioxidant, N-Acetyl-l-Cysteine, Reduces Global Cerebral Ischemia-Induced Neuronal Death

“…Under the ischemic condition, disruption of brain homeostasis is disturbed and cell death mechanisms are initiated. This cerebral injury leads to an alteration in ionic balance within the intra-extracellular space [ 6 ], reactive oxygen species (ROS) production [ 7 ], microglia [ 8 ] and astrocyte [ 9 ] activation, zinc accumulation [ 10 ], and neuronal cell degeneration [ 11 , 12 , 13 ] in the brain. Blockage of blood flow to the brain by ischemic insult causes tissue infarction, dysfunction of ionic balance, and intracellular calcium overload [ 14 ].…”

The Effects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury

“…In general, previous studies showed that PDK inhibits PDH via phosphorylating PDH after brain injuries, such as ischemia or epilepsy, thereby restricting the pyruvate oxidation (PO) pathway available to brain cells. As a result, under this pathological condition, the citric acid cycle cannot proceed and the production of ATP decreases, leading to cell death [26,27].…”