**The E** ff**ects of Sodium Dichloroacetate on Mitochondrial Dysfunction and Neuronal Death Following Hypoglycemia-Induced Injury**

#### **A Ra Kho 1, Bo Young Choi 1, Song Hee Lee 1, Dae Ki Hong 1, Jeong Hyun Jeong 1, Beom Seok Kang 1, Dong Hyeon Kang 2, Kyoung-Ha Park 3, Jae Bong Park 4 and Sang Won Suh 1,\***


Received: 15 March 2019; Accepted: 1 May 2019; Published: 1 May 2019

**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 e ffect 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 sugges<sup>t</sup> that DCA may have the therapeutic potential to reduce hippocampal neuronal death after hypoglycemia.

**Keywords:** hypoglycemia; sodium dichloroacetate; pyruvate dehydrogenase kinase; pyruvate dehydrogenase; oxidative stress; neuron death
