Enhancing Metabolic Imaging of Energy Metabolism in Traumatic Brain Injury Using Hyperpolarized [1-13C]Pyruvate and Dichloroacetate

Abstract

Hyperpolarized magnetic resonance spectroscopic imaging (MRSI) of [1-13C]pyruvate metabolism has previously been used to assess the effects of traumatic brain injury (TBI) in rats. Here, we show that MRSI can be used in conjunction with dichloroacetate to measure the phosphorylation state of pyruvate dehydrogenase (PDH) following mild-to-moderate TBI, and that measurements can be repeated in a longitudinal study to monitor the course of injury progression and recovery. We found that the level of 13C-bicarbonate and the bicarbonate-to-lactate ratio decreased on the injured side of the brain four hours after injury and continued to decrease through day 7. Levels recovered to normal by day 28. Measurements following dichloroacetate administration showed that PDH was inhibited equally by PDH kinase (PDK) on both sides of the brain. Therefore, the decrease in aerobic metabolism is not due to inhibition by PDK.

DCA Protects against Oxidation Injury Attributed to Cerebral Ischemia‐Reperfusion by Regulating Glycolysis through PDK2‐PDH‐Nrf2 Axis

“…Previous studies have shown that DCA is a pharmacological agent that activates PDH by inhibiting PDK and also shows significant neuroprotective potential. The administration of DCA has been suggested to facilitate local lactic acid removal [ 32 ], tumor therapy [ 33 ], and pulmonary hypertension [ 34 ]. However, the protective effect, molecular mechanism, and blood-brain barrier permeability of DCA in cerebral IS and I/R injury have been rarely investigated.…”

Tracing the path of disruption: 13C isotope applications in traumatic brain injury‐induced metabolic dysfunction

“…122 Furthermore, dichloroacetate coadministration, a PDH kinase inhibitor, showed no difference in PDH activity, indicating aerobic metabolism reduction is not due to PDH kinase inhibition. 53 Interestingly, all studies using 1-13 C-pyruvate to date have employed MRSI as the detection method, highlighting its potential as an early, noninvasive imaging modality for identifying cerebral metabolic changes in otherwise radiographically normal TBI patients. 55 Further, the use of such technology in tandem with machine learning workflows was recently shown to be capable of predicting long-term behavior changes after TBI in animals that otherwise lack detectable changes in conventional imaging at the same timepoint, 137 which suggests isotope tracing may be a powerful approach to better study the link between TBI and the elevated risk of developing long-term neurobehavioral sequelae including mental health disorders 138 and dementia, 139 among others.…”

“…Pyruvate, the product of glycolysis, can be converted into lactate or acetyl CoA. TBI has been found to inhibit both the expression and activity of pyruvate dehydrogenase (PDH) 51–53 in rats, potentially shifting pyruvate metabolism toward lactate. Clinical studies suggest impaired mitochondrial pyruvate metabolism in TBI, leading to decreased aerobic respiration at the location of injury 54,55 .…”

Neuroprotective Effects and Therapeutic Potential of Dichloroacetate: Targeting Metabolic Disorders in Nervous System Diseases

“…43 DeVience et al assessed the extent of traumatic brain injury in rats by magnetic resonance spectroscopy (MRS) of hyperpolarized [1-13C] pyruvate and found that DCA (200 mg/kg) increased the bicarbonate/lactate ratio on both sides of the brain and attenuated the inhibition of PDH, but they did not assess whether DCA protects neurons. 44 DCA (50 and 100 mg/kg/day) was observed to shorten the latency to seizures in a second-hit flurothyl test in the mouse Figure 2 The role of DCA in cerebral ischaemia-reperfusion injury. Notes: When there is ischaemia-reperfusion injury, ATP deficiency causes the cell membrane ion pump to malfunction and intracellular calcium levels to rise.…”