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

Human 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: βHydroxybutyrate (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 administration of a KD [16]. Taken together, these findings suggest that neurons may resist to depolarization through ionic gradient and rest potential homeostasis, which explains the analogy between anticonvulsant mechanisms of orally administered ketone bodies and KD. Epilepsy represents one of the most frequent neurological pathologies as it affects about 43 million people worldwide. It results from a variety of CNS disorders and can be determined by vascular damages, genetic factors or malformations, cancers, pre-/post-natal injuries, traumatic brain injury. It has been demonstrated that the KD is one of the most effective non-pharmacological approaches in refractory epilepsy [17], although it is still unknown to and underestimated by many neurologists. Furthermore, the KD can be associated with classic antiepileptic drugs, thus significantly increasing their therapeutic results [18]. The KD induces a consistent increase in blood ketone concentration, notably AcAc and acetone [19] and it has been shown fully effective in about 50% of epileptic cases (complete seizure elimination), and partially efficient in the remaining half of patients, where it significantly improves their quality of life [20]. On another note, ketones show a neuroprotective effect also against neurodegenerative pathologies characterized by deficits in glucose metabolism, since impairment of mitochondrial function represents the main cause of a high number of neurological diseases. In fact, the following findings were published in response to ketosis: Increased cell survival and decreased seizure frequency in kainate-induced seizure models [21]; consistent reduction in lesion volume after TBI induction [22]; suppressed inflammatory cytokines and chemokines in an experimental model of multiple sclerosis [23] increase in motor neuron number in ALS transgenic models [3,24]. Notably, studies on ALS mouse models have suggested that targeting energy metabolism with metabolic therapy may prolong survival and quality of life in ALS patients. However, to date there are no clinical trials underway to test such metabolic therapies.