The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury

Abstract

This article is available online at http://www.jlr.org setting ( 2, 3 ). Thus, there is a signifi cant need to identify better strategies to improve global outcome after TBI. In addition, given the inherent differences between the developing brain in which dynamic processes such as synaptogenesis, myelination, and plasticity are ongoing, and the mature adult brain in which these processes have been completed, any potential neuroprotective treatment must be evaluated in an age-specifi c manner. To that end, we discuss the changes in cerebral glucose metabolism, which have been described in the aftermath of TBI, the age-related variation of this metabolic dysfunction, and the potential of using the natural ketone metabolism mechanisms to ameliorate these problems and improve global outcome. METABOLIC DYSFUNCTIONS AFTER TBIUpon impact, rapid movement of the brain within the skull initiates a series of neurochemical disruptions that alter cerebral metabolism. Within minutes after injury, the ionic equilibrium across the neuronal membranes is disrupted, with injury severity-dependent increases in the concentration of extracellular potassium and glutamate, as well as intracellular calcium accumulation ( 4, 5 ). This disruption of ionic equilibrium requires cellular energy to reestablish homeostasis, which is refl ected by increases in cerebral glucose uptake observed within 30 min after adult rodent fl uid percussion (FP) injury ( 6 ) and within 8 days after human TBI ( 7 ). This transient increase in glucose uptake is also known as "hyperglycolysis" and is followed by a prolonged period of glucose metabolic depression. These cerebral metabolic changes are a hallmark response described in both experimental and clinical brain trauma. Nationally, the incidence of traumatic brain injury (TBI) exceeds that of all other health diseases with an annual incidence of 1.7 million new cases ( 1 ). It is an injury that affects both genders across all age groups, producing long-term disabilities that negatively impact families and society. Recent years have seen a substantial increase in public awareness of the long-term cognitive, emotional, and functional consequences of TBI. However, several potential neuroprotective treatments, such as therapeutic hypothermia, have produced disappointing results when tested in the clinical

Age and Diet Affect Genetically Separable Secondary Injuries that Cause Acute Mortality Following Traumatic Brain Injury in Drosophila

“…This finding suggests that mortality is determined by metabolic processes whose activity changes with age. A candidate metabolic process is ketosis, in which energy is provided by ketones rather than glucose (Prins and Matsumoto 2014). Fasting, which upregulates ketosis, is neuroprotective in a rat TBI model (Davis et al 2008).…”

Ketogenic diet and its impact on mental processes of working population

“…In animal models these devastation to mitochondria can be alleviated by KB (Baxter et al, 2014). Postoperatively, KD could also be used with adult patients who suffered head trauma (Prins et al, 2014).…”

Commentary and Update on “The Mitochondrial Permeability Transition Pore Provides a Key to the Diagnosis and Treatment of Traumatic Brain Injury”

“…The increase in brain temperature after TBI is most economically explained by the opening of the mitochondrial membrane permeability transition pore [1,9] with conversion of the energy of the electron transport system from ATP generation to heat production. This accounts for the decrease in brain phosphorylation potential during TBI and for the increase in mitochondrial Ca 2+ and Mg 2+ associated with this pore opening [10].…”

“…Closing of the MPTP can be achieved by increasing the energy of ATP hydrolysis by the metabolism of ketone bodies due to administration of ketone body esters or by feeding a ketogenic diet [9,17]. A ketone ester supplement is perhaps preferred to a ketogenic diet due to the difficulties and complications of the diet and the time it takes to enter a state of ketosis.…”