The findings of recent investigations have suggested that ca

The findings of recent investigations have suggested that caloric restriction prevents age-related neuronal damage and may be useful in the prevention and treatment of AD [14]. Hypotheses linking caloric restriction to cognitive capability include anti-inflammatory mechanisms, reduction of neural oxidative stress, promotion of synaptic plasticity as well as induction of various stress and neurotrophic/neuroprotective factors [14]. Caloric restriction may also prevent Aβ neuropathology in AD transgenic animal models [14]. A relative recent dietary approach to the treatment of AD is the administration of ketogenic diets.
Development of ketogenic diets During infancy and early childhood, ketone bodies play an important role beside glucose as oxidizable substrates and energy source for the brain [15] since their blood plasma concentrations are high and an abundance of monocarboxylic bupropion hydrochloride transporters render the blood–brain barrier greatly permeable to ketone bodies [16]. In adult humans, high ketone body concentrations are found during fasting and on a high-fat diet. In addition, the permeability of the blood–brain barrier increases with fasting [16]. Ketone bodies when present at sufficient concentrations to saturate metabolism can support most, if not all, basal (non-signaling) neuronal energy needs and up to approximately half of the activity-dependent oxidative needs of neurons [17]. When food was scarce, ketosis may have been a survival mechanism during human evolution [18]. Foods containing large amounts of carbohydrates have relatively recently become a part of the human diet and may be more evolutionarily discordant than high fat diets [19]. High carbohydrate diets stimulate insulin signaling and lead to a suppression of lipid metabolism and ketogenesis [20]. The evolutionary switch to diets high in carbohydrates (ketodeficient diet) has been hypothesized to play a role in the development of AD [21]. It has long been known that fasting has anticonvulsant properties. The ketogenic diet was developed in the 1920s to mimic the physiological alterations observed in prolonged fasting [22] when energy is mainly derived from the utilization of body fat or dietary fat. This diet was successfully used as a therapeutic approach for seizures [23]. Due to the availability of antiepileptic drugs the ketogenic diet was not in use for decades, but was in favor again in the 1990s, particularly in the therapy of pharmacoresistant epilepsy. The ketogenic diet is very high in fat and low in carbohydrates and is believed to simulate the effects of starvation by primarily metabolizing fat as energy supply [24]. While fasting the organism metabolizes stored body fat via lipolysis and the ensuing β-oxidation of fatty acids leads to the production of acetoacetate, β-hydroxybutyrate and acetone which can easily cross the blood–brain barrier. These ketone bodies can be used as precursors for the generation of adenosine triphosphate (ATP). The ketogenic diet has now become an established and effective nonpharmacological treatment for epilepsy [25–27]. A number of patients with intractable epilepsy have been shown to become seizure-free or to have a significant reduction in seizure frequency during the administration of a ketogenic diet and even following the discontinuation of the diet, suggesting disease-modifying effects in some patients with epilepsy [27]. Several mechanisms underlying the anticonvulsive effects of ketone bodies have been proposed [27], including changes in ATP production, altered brain pH affecting neuronal excitability, direct inhibitory effects of ketone bodies or fatty acids on ion channels, and shifts in amino acid metabolism [28–30]. Since at least some glucose is required for the synthesis of glutamate and the maintenance of homeostasis during glutamatergic activity [31], a ketogenic diet very low in carbohydrates may prevent seizures by compromising the formation of the excitatory neurotransmitter glutamate (for further details see Ref. [32]). This hypothesis is supported by the fact that the replacement of glucose by β-hydroxybutyrate in the medium decreases glutamate availability in cultured neurons [33].