Abstract
Our previous studies demonstrated that some degree of neuronal death is caused by hypoglycemia, but a subsequent and more severe wave of neuronal cell death occurs due to glucose reperfusion, which results from the rapid restoration of low blood glucose levels. Mitochondrial dysfunction caused by hypoglycemia leads to increased levels of pyruvate dehydrogenase kinase (PDK) and suppresses the formation of ATP by inhibiting pyruvate dehydrogenase (PDH) activation, which can convert pyruvate into acetyl-coenzyme A (acetyl-CoA). Sodium dichloroacetate (DCA) is a PDK inhibitor and activates PDH, the gatekeeper of glucose oxidation. However, no studies about the effect of DCA on hypoglycemia have been published. In the present study, we hypothesized that DCA treatment could reduce neuronal death through improvement of glycolysis and prevention of reactive oxygen species production after hypoglycemia. To test this, we used an animal model of insulin-induced hypoglycemia and injected DCA (100 mg/kg, i.v., two days) following hypoglycemic insult. Histological evaluation was performed one week after hypoglycemia. DCA treatment reduced hypoglycemia-induced oxidative stress, microglial activation, blood–brain barrier disruption, and neuronal death compared to the vehicle-treated hypoglycemia group. Therefore, our findings suggest that DCA may have the therapeutic potential to reduce hippocampal neuronal death after hypoglycemia.
Highlights
Hypoglycemia is a potentially serious condition that occurs when blood glucose levels quickly fall below a specific threshold concentration
We found that DCA treatment inhibited pyruvate dehydrogenase kinase (PDK) and significantly reduced oxidative stress, microglial activation, blood-brain barrier (BBB) disruption, and hippocampal neuronal death after severe hypoglycemia via enhancing pyruvate dehydrogenase (PDH) activation
We hypothesized that PDKs activation blocks entry of pyruvate into the citrate acid cycle in mitochondria, leading to reduction of ATP formation, and causes neuronal cell death in hypoglycemia
Summary
Hypoglycemia is a potentially serious condition that occurs when blood glucose levels quickly fall below a specific threshold concentration. The most common cause of hypoglycemia is misuse of medications such as insulin and sulfonylureas to control blood glucose levels [1,2]. Medications that cause blood glucose levels to fall sharply or repeatedly can lead to hypoglycemic shock. In these cases, the first treatment for patients who present at the hospital in a hypoglycemic state of shock is to rapidly raise blood glucose levels, which is essential for resuscitating the patient and impossible to avoid. This study is important to identify means to minimize neuronal cell death caused by hypoglycemia and glucose reperfusion, which is performed as an essential step in treating hypoglycemia
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