properties • high-fat, adequate-protein, low-carbohydrate diet . • The diet forces the body to burn fats rather than carbohydrates. • The original therapeutic diet provides just enough protein for body growth and repair, and sufficient calories to maintain the correct weight for age and height. This classic ketogenic diet contains a 4:1 ratio by weight of fat to combined protein and carbohydrate. This is achieved by excluding high-carbohydrate foods. • the liver converts fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source. • A typical ketogenic diet meal
THERAPAUTICS • 30 % of patients become seizure free. 60 % of patients experience significant benefit. • The onset of seizure control is typically slow, probably reflecting the induction of the transporters and enzymes required for effective utilization of ketone bodies by the brain. • In contrast, seizure protection is lost quite quickly when the ketogenic diet is “broken” by a supply of sugar by having a candy bar), seizure protection is lost in the course of tens of minutes.
THERAPAUTICS • broad anticonvulsant effects, as it is able to control seizures of many different types. In this way it is a more effective anticonvulsant therapy than any of the currently available antiepileptic drugs • Ketogenic diet is used as a second line treatment for refractory epilepsy ( don’t respond to 2-3 different anticonvulsants).
weight loss Kennedy A R et al. Am J PhysiolEndocrinolMetab 2007;292:E1724-E1739
Reduced brain excitability • Augmentation of ketone bodies production • The metabolic changes associated with decreased glucose oxidation
Reservations • the10 mM concentration of acetoacetate directly dialyzed into the rat brain was considerably higher than the effective concentrations required for inhibition of VGLUT2 • organotypic hippocampal slice cultures chronically exposed to BHB were not protected from pharmacologically induced epileptiformactivity. • acetoacetate rapidly breaks down to acetone or is converted to BHB, so it remains to be shown whether acetoacetate levels in the brain during dietary therapy are sufficient to inhibit VGLUT2 chronically
the ketogenic diet suppresses seizures in mice through adenosine A1 receptors • Adenosine is a well established and powerful anticonvulsant • deletion of A1Rs and increased adenosine clearance by elevated adenosine kinase (ADK) both cause spontaneous intrahippocampalelectrographic seizures and increase the brain’s susceptibility to injury
theketogenic diet suppresses seizures in mice through adenosine A1 receptors
K channels • K channels (KATP channels) Best-known for their role in controlling insulin secretion from pancreatic -cells • KATPchannels are also widely expressed in central neurons.
Ketone bodies mediate excitability as a result anincrease mitochondrial metabolismand decrease glycolysis
BAD protein • A protein with dual functions in apoptosis and glucose metabolism. • BAD modifications (by phosphorylation)that reduce glucose metabolism produce a marked increase in the activity of metabolically sensitive KATP channels in neurons. • phosphorylation is required for mitochondrial metabolism of glucose. • Seizure resistance of knockout BAD mice is reversed by genetic ablation of the KATP channel.
selective switch in fuel preference from glucose to ketone body consumption
Enhancment of the hippocampal redox status • glutamate cysteine ligase – the rate limiting enzyme of glutathione production • Reduced COA is an indicator of the mitochondrial redox status • lipoicacid - a thiolantioxidant.