Health Scope. 2020 May; 9(2):e86578. doi: 10.5812/jhealthscope.86578. Published online 2020 May 31. Review Article The Role of Ketone Bodies in Improving Neurological Function and Efficiency Deepanshu Naithani 1 and Santosh Kumar Karn 1, * 1Sardar Bhagwan Singh University, Balawala, Dehradun, India *Corresponding author: Department of Biochemistry and Biotechnology, Sardar Bhagwan Singh University, Balawala, Dehradun, India. Email: [email protected] Received 2019 October 05; Accepted 2020 January 09. Abstract Neurological coordination is essential for performing biological and mechanical activities achieved by the cooperation of biomolecules such as carbohydrates, lipids, and proteins. It plays an important role in energy production, which can be fascinat- ingly improved by ketone bodies. Ketone bodies are small, water-soluble lipid molecules by shifting the glycolytic phase KBs directly enters into the tricarboxylic acid cycle for ATP synthesis. It leads to the production of much more energy levels than a single molecule of glucose. Therefore, it could have a profound effect on neuro-metabolism as well as bioenergetics of ATP production. These neuro- enhancement properties are useful for epilepsy, Alzheimer’s, and several neurocognitive disorders treatment. Interestingly, the cancer cells cannot use it for efficiently energy production results in decreasing cancer cells viability. This review summarized ke- tone bodies generation, related imperative effects on normal cells, and more importantly its application in various neurological disorders treatment by rising neuronal functions. Keywords: ATP, Ketones Bodies, Ketogenic Diet, Metabolic Function, Neurons, Physiology 1. Context proved by ketogenic diet or medium length chain glyc- eride diet affected diseases, i.e., Alzheimer’s disease, motor Ketone bodies (KBs), characterized as lipid particles, dysfunction, epilepsy, Parkinson disease, metabolic syn- water-soluble formed inside the liver tissue, can be utilized dromes, glycogen storage disease, Spinal cord injury and as a secondary source of energy if glucose is not able to pro- Autism in the rat models (5). In this line, extrahepatic tis- vide enough energy. They show possessing the potential to sues are also able to oxidize KBs, contributing to efficient cross the blood-brain barrier (BBB) and the placental bar- energy metabolism (6). Recent studies on the regulation rier. Acetone, beta-hydroxybutyrate, and acetoacetate are of extracted KBs from hepatocytes or perfused liver and rat well-known ketone bodies which were generated during models in fed to starve state, showed that when the KBs the absence of glucose or when the body cannot utilize it concentration exceeds from normal levels, for example, in as energy in type 1 diabetes (1). Indeed, KBs should not be diabetes type 1, leads to a pathologic state known as ke- considered as a simple energy molecule required during toacidosis. The genes which generally play a key role in synthesis of membrane in physiological development (2). modulated KBs formation and utilization include Hmgcs2, They are formed by the breakdown of fatty acids during a CPT1A, FABP, LCAD, MCAD, and MCT1, also transcription fac- low glucose intake or under a ketogenic diet (3). In fact, tors such as SREBF1, PPARG, CEBPA, and PPARα. Currently, KBs are produced during a ketogenic diet or due to glu- the improvement of neurological efficiency via KBs in a cose starvation, which can influence many metabolic and regulatory manner with specific diets such as ketogenic regulatory enzymes, and subsequently substrates result in diet and its utilization for treating certain neurological dis- a neuroprotective, anti-oxidant, anti-inflammatory, anti- orders and cancer seems to be an interesting issue to fo- seizure, hyper excitability as well as synchrony in neurons cus. Overall, KBs, as an alternative energy source for sur- (4). A ketogenic diet includes low carbohydrate- protein vival during food deprivation, show the potential to help and high-fat meals consumption leading towards a starved improving body control and coordination as well as the state. KBs are considered the more efficient alternative en- treatment of multiple diseases. ergy source in the brain and mitochondrial metabolism. It has been proved that the motor functions could be im- Copyright © 2020, Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited. Naithani D and Karn SK 2. Brain Metabolic Functions With/Without Ketone defensive arrangements to limit harm, secure the heredi- Bodies and Its Effect on Other Metabolic Processes tary components such as DNA and transferring across the generations should be unchanged (15). Experimental stud- Glucose is generally utilized as the main source of ies on yeast showed that when a single-celled being is trans- fuel, broken down subsequently during the glycolysis ported from carbon or alcohol medium to H2O, it devel- pathway (7), which transported with the glucose trans- ops further resistant to the numerous stressful conditions porters (GLUT), including different isoforms as well as ki- and survives for a long time (16). Responding against food netic constants inside the brain (8). Once glucose en- shortage, cells of yeast downregulate one or more primary ters into the neuronal cytosol, is able to easily participate ways, preliminary by Ras-PKA pathway to blood glucose re- in the different metabolic pathways comprising glycoly- sponse and secondary Tor-S6K pathway for amino acid re- sis, tricarboxylic acid (TCA) cycle and electron transport sponse, and serine-threonine kinase pathway inhibition, chain (oxidative/non-oxidative phosphorylation), the pen- the stress resistance transcription factors like Gis1 and tose phosphate or hexose monophosphate shunt pathway Msn2/4, which are needed for the defensive mechanisms, (PPP) and synthesis of glycogen (9). During glycolysis, to an extent by expanding the stress opposition qualities glucose is oxidized and converted into the two molecules in genes including superoxide dismutase (SOD) and cata- of pyruvate by phosphofructokinase-1, (hexokinase (HK), lase (17). Outstandingly, when starving yeast cells reach pyruvate kinase, which are greatly expressed inside the a hypo-metabolic condition which enables yeast cells to neuronal cytoplasm (10). In this context, the TCA (tri- limit the utilization of food sources reservation and is also carboxylic acid) cycle plays a very important role in the able to gather abnormal amounts of the ketone body-like formation of substrates required for electron transport aceto-acetate, similarly for collection of ketone bodies in chain and, ultimately Adenosine Triphosphate (ATP) gen- the mammals (18). Therefore, under stress conditions such eration inside the mitochondria (11). Given that the brain as starvation or food deprivation, ATP consumption de- extremely needs to the glucose-derived energy, it is used creases (19). In a similar way, in respond against starvation, primarily in the brain for energy production, and the neu- mammalian cells enter into a non-growing or a slowly- rons use nearly 70% of the ATP in the brain. This energy growing condition and put vitality assets into the cell de- necessity can decrease during neurodegenerative disor- fence facing different problems. Short amounts of insulin ders, which decrease glucose utilization/uptake and show like growth factor (IGF-1) diminish mitogenic signalling a decrease in mitochondrial activity which results in a de- pathways within the cells, down-regulating both of the creased ATP formation (12). During a failure in the kinet- main pathways downstream of IGF1R which are managed ics of foods, further calories required to maintain nor- by Akt and Ras, as well as the ability to incite cell division mal functions of body. After a few days under a starved cycle stimulated by p21 and p53 induction (20) and tran- state, the body begins to generate KBs as a main source scription of other defensive factors such as Egr1 and FOXO, for producing energy. The brain tissue is capable of deriv- to control SOD, and other stress resistance genes (21). ing two-third of its metabolic processes from ketone oxida- tion (13). In fact, KBs enter the brain tissue through mono- 3. Cellular Modification and Related Metabolisms carboxylate transporters (MCT) with the higher rates of ex- pression and activity in the brain of new-born than the Physical changes of micro-villi and epithelial tissues matured rats. Beta-hydroxybutyrate (BHB) and acetoac- within each side of the gastrointestinal tract are observed etate are absorbed by the brain and used proficiently as inside the hens, maintained in fasting state for 12 h which substrates for energy production, in protein and lipid bio- is extended till 20 days, upon each fasting period. After formation, which are the most important ways required the first 24 hours of starving, micro-villi displays a signif- in the dynamic brain development. It has also been found icant decrease inside the duodenum in terms of the vil- that KBs about 30% - 70% aggregate energy metabolism in lus size, slighter decrease in the jejunum. While there is the cerebrum of young rodents. Pertinent studies show not a significant decrease in the height of microvilli in that single-cell organisms like bacteria, insects and some