Ketone Esters partially and selectively rescue mitochondrial bioenergetics after acute cervical spinal cord injury in rats: A time-course

Abstract

Abstract Spinal cord injury (SCI) pathology and pathophysiology can be attributed to both primary physical injury and secondary injury cascades. Secondary injury cascades involve dysregulated metabolism and energetic deficits, which are directly linked to compromised mitochondrial bioenergetics. Rescuing mitochondrial function and reducing oxidative stress are associated with neuroprotection. In this regard, ketosis after traumatic brain injury (TBI), or after SCI, improves secondary neuropathology by decreasing oxidative stress, increasing antioxidants, reducing inflammation, and improving mitochondrial bioenergetics. Here, we follow up on our previous study and have used an exogenous ketone monoester, (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE), as an alternative to a ketogenic diet, focusing on mitochondrial function between 1 and 14 days after injury. Starting 3 hours following a C5 hemi-contusion injury, animals were fed either a standard control diet (SD) or a ketone ester diet (KED) combined with KE administered orally (OKE). We found that mitochondrial function was reduced after SCI at all times post-SCI, accompanied by reduced expression of most of the components of the electron transport chain (ETC). The KE rescued some of the bioenergetic parameters 24 hours after SCI when BHB concentrations were ~ 2 mM, but most of the beneficial effects were observed at 2 weeks after injury with BHB concentrations reaching values of 4–6 mM. To our knowledge, this is the first report of beneficial effects of KE in rescuing mitochondrial function after SCI and demonstrates the suitability of KE to ameliorate the metabolic dysregulation that occurs after traumatic SCI without requiring a restrictive dietary regime.