I. high-fat, adequate-protein, low-carbohydrate diet. II. The diet forces the body to burn fats...
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THE KETOGENIC DIET
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PROPERTIESI. high-fat, adequate-protein, low-carbohydrate diet .
II. The diet forces the body to burn fats rather than carbohydrates.
III. 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.
IV. the liver converts fat into fatty acids and ketone bodies. The ketone bodies pass into the brain and replace glucose as an energy source.
V. A typical ketogenic diet meal
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THERAPAUTICSI. 30 % of patients become seizure free. 60 % of patients
experience significant benefit.
II. 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.
III. 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.
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THERAPAUTICSIV. 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
V. Ketogenic diet is used as a second line treatment for refractory epilepsy ( don’t respond to 2-3 different anticonvulsants).
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WEIGHT LOSS
Kennedy A R et al. Am J Physiol Endocrinol Metab 2007;292:E1724-E1739
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REDUCED BRAIN EXCITABILITY
I. Augmentation of ketone bodies production
II. The metabolic changes associated with decreased glucose oxidation
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PRODUCTION OF KETONE BODIES
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METABOLIC CONTROL OF VESICULARGLUTAMATE TRANSPORT AND RELEASE
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METABOLIC CONTROL OF VESICULARGLUTAMATE TRANSPORT AND RELEASE
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RESERVATIONSI. the10 mM concentration of acetoacetate directly dialyzed
into the rat brain was considerably higher than the effective concentrations required for inhibition of VGLUT2
II. organotypic hippocampal slice cultures chronically exposed to BHB were not protected from pharmacologically induced epileptiform activity.
III. 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
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THE KETOGENIC DIET SUPPRESSES SEIZURES IN MICE THROUGH ADENOSINE A1 RECEPTORS1. Adenosine is a well established and
powerful anticonvulsant
2. deletion of A1Rs and increased adenosine clearance by elevated adenosine kinase (ADK) both cause spontaneous intrahippocampal electrographic seizures and increase the brain’s susceptibility to injury
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THE KETOGENIC DIET SUPPRESSES SEIZURES IN MICE THROUGH ADENOSINE A1 RECEPTORS
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K CHANNELS
I. K channels (KATP channels) Best-known for their role in controlling insulin secretion from pancreatic -cells
II. KATP channels are also widely expressed in central neurons.
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KETONE BODIES MEDIATE EXCITABILITY AS A RESULT AN INCREASE MITOCHONDRIAL
METABOLISM AND DECREASE GLYCOLYSIS
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BAD PROTEINI. A protein with dual functions in apoptosis and glucose metabolism.
II. BAD modifications (by phosphorylation) that reduce glucose metabolism produce a marked increase in the activity of metabolically sensitive KATP channels in neurons.
III. phosphorylation is required for mitochondrial metabolism of glucose.
IV. Seizure resistance of knockout BAD mice is reversed by genetic ablation of the KATP channel.
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SELECTIVE SWITCH IN FUEL PREFERENCE FROM GLUCOSE TO
KETONE BODY CONSUMPTION
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BAD MUTANT MICE RESISTANT TO SEIZURES
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A SHIFT FROM GLYCOLYSIS TO THE PENTOSE
PHOSPHATE PATHWAY
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glutamate cysteine ligase – the rate limiting enzyme of glutathione production
Reduced COA is an indicator of the mitochondrial redox status
lipoic acid - a thiol antioxidant.
ENHANCMENT OF THE HIPPOCAMPAL REDOX STATUS
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ENHANCMENT OF THE HIPPOCAMPAL REDOX STATUS
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PROTECTION OF MITOCHONDRIAL DNA AGAINST OXIDATIVE STRESS
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PROPOSED MECHANISIMS
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