The Ketogenic Diet Approach as Metabolic Treatment for a Variety of Diseases

Abstract

EditorialHuman brain derives over 60% of its energy from ketones when glucose availability is limited. After prolonged periods of fasting or Ketogenic Diet (KD), the whole body utilizes energy obtained from Free Fatty Acids (FFAs) released from adipose tissue. However, the brain is not capable to obtain significant energy from FFAs, thus hepatic ketogenesis converts them into ketone bodies: β-Hydroxybutyrate (BHB) and acetoacetate (AcAc), while a percentage of AcAc spontaneously decarboxylates to acetone [1]. To date, it has been broadly demonstrated how the metabolic state of mild ketosis, which can be induced through KD administration, calorie restriction or fasting, represents a valid tool for the metabolic management of epilepsy and a number neurodegenerative diseases [2], Amyotrophic Lateral Sclerosis (ALS) [3], and some types of cancer [4,5]. In addition, nutritional treatments represent an effective alternative where pharmaceutical approaches fail or produce unbearable side effects and costs for public health worldwide. However, before analyzing how benefits from therapeutic ketosis could be exploited, let us mention some pivotal concepts about metabolism. Under normal conditions and mostly in western societies, a healthy brain utilizes glucose as primary energy source, which unbalance can lead to a number of neurodegenerative disorders often associated with mitochondrial impairment and glucose transport-related dysfunctions, such as in epilepsy, Traumatic Brain Injury (TBI), Parkinson's and Alzheimer's diseases [6,7]. Ketone bodies and Krebs cycle intermediates represent the best fuels for brain and other organs. In fact, through their utilization, impaired glucose metabolism may be bypassed and their neuroprotective properties may be exploited [8]. However, neuroprotective mechanisms of ketosis are currently object of studies as mechanisms of action are still not sufficiently understood. It has been shown that ketone bodies are neuroprotective as they induce a consistent increase in mitochondrial biogenesis regulating the synaptic function, and also generate ATP increases, thus reducing the reactive oxygen species production in neurological tissues [9,10], and notably inhibit superoxide synthesis in primary rat neuronal cultures exposed to hyperoxia [11]. Moreover, the main reason why the KD has been proven so effective as an anticonvulsant aFpproach is because it significantly reduces the metabolism of glucose [12]. In addition, Ma and colleagues [13] demonstrated that, at physiological concentrations, BHB and AcAc reduce spontaneous discharges of GABAergic neurons in the rat substantia nigra, through ATP-sensitive potassium channels.Also, a reduction of total CNS aspartate levels in association with an increase of glutamate concentrations was found during ketosis, observing a significant increase of decarboxylated glutamate to GABA, the main inhibitory neurotransmitter [14,15]. Moreover, a remarkable increase in mitochondrial transcription enzymes and proteins was observed in rat hippocampus after the...