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Mechanisms of Ketogenic Diet action COGS 163: FLAMING DINOS

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Mechanisms of Ketogenic Diet action COGS 163: FLAMING DINOS What is the keto diet? High fat, low carb, adequate protein Force body to burn fats not carbs NOT Atkins Diet Used to treat epilepsy HOW A NORMAL
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Mechanisms of Ketogenic Diet action COGS 163: FLAMING DINOS What is the keto diet? High fat, low carb, adequate protein Force body to burn fats not carbs NOT Atkins Diet Used to treat epilepsy HOW A NORMAL BODY PROCESSES GLUCOSE GLYCOLYSIS 2 ADP + 2 (P) 2 NAD+ 2 ATP 2 NADH+ 2H+ KREB S CYCLE (SIMPLIFIED) ELECTRON TRANSPORT CHAIN WHAT HAPPENS IN KETOSIS? Reduced blood glucose levels Fatty acid oxidation in liver Production of ketone bodies = alternative energy source to glucose in brain OVERVIEW OF GLUCOSE REGULATION AMPLE CARBS Glucose = Co2, acetylcoa is intermediate goes into krebs ATP NO CARBS Fatty acids= acetylcoa (not recycled in Krebs) because OAA all used to make more glucose ACCUMULATION OF ACETYLCOA ACTIVATES KETOGENESIS Historical and Clinical Perspectives Mild dehydration necessary Decreased ph (acidosis) Approved Dietary Therapies Ketogenic Diet Modified Atkin s Diet LowGlycemic Index Treatment Animal models: A Cautionary tail In some studies KD works, sometimes it doesn t You can t do a crosscomparison because of highly variable methodologies Acute Models vs. Chronic Models Inducing seizures vs. epileptic mice Acute Animal Models (the crosscomparison that wasn t meant to be...) Treatment Type % Fat Who? Length Effect Corneal electroshock electric 55% JM mice short KD: protective effects Hydration electroshock electric 55% JM mice short KD: less protective than control Maximal electroshock electric 78% AM rats long KD: ^ severity, less WG Pentylenetetrazol chemical 78% AM rats long KD: elevated threshold, Less WG Bicuculline chemical 78% JM rats long KD: Fewer threshold seizures, longer seizure onset time Semicarbazide chemical 55% JM mice short KD: more protective than control Kainate chemical 81% AM mice short KD: Delay seizure onset, decrease Hippocampal loss Fluorothyl chemical 91% JM/AM mice short KD: less WG+ ^ thrshld in JM Maximal electroshock electric 76% JM/AM mice short KD: increased threshold to shock Chronic Animal Models (Ditto) Treatment Type % Fat Who? Length Effect Kainateinduced status epilepticus chemical 78.8% JM Rats short KD: less WG, worse water maze performance Succinic semialdehyde dehydrogenase chemical 80% J Mice Long KD: WG, fewer seizures EL (seizuresusceptible inbred) genetic Injected BHB JF Mice short ACA, acetone: protective BHB: depends + mildly toxic DBA: dose dependent protection Kcnalnull mice genetic 86% J Mice short KD: fewer seizures Ketone bodies themselves? Seizure control lost when ketosis breaks Ketone body plasma levels correlate with seizure protection Mechanisms? Interconversion of ACA to Acetone and BHB BHB and ACA open KATP channels of GABAergic neurons in SNr ACA inhibits vesicular glutamate transporters Not sure though! KATP channels open ACA inhibits Glu transport Age dependence? KD more effective in children? Higher fat content in breast milk need efficient mechanisms Higher expression of MCT1 and MCT2 in infants/children Who knows though? Age dependence? Ketone Bodies Inhibit GABAergic Mediated Inhibition Decrease seizures? Noradrenergic system, Leptin, and KD NE reuptake inhibitors prevent seizures (rat model) NE lacking mice have no response to KD KD increases NE levels in hippocampus by twofold Leptin modulates neuronal excitability and suppresses seizures KD increases leptin Polyunsaturated Fatty Acids PUFAs decrease neuronal excitability PUFA levels elevated during KD from clinical evidence PUFAs and seizure control? Not sure! PUFA load, treatment duration, degree of ketosis as important variables PUFAs activate PPAR could be anticonvulsant Metabolic Mechanisms Consistent with increased energy reserves, ketogenic diet fed animals were highly resistant to the metabolic stress induced by low glucose conditions Ketogenic Diet: ATP, bioenergetic substrates, cerebral energy reserve, brain adenine metabolic enzymes and mitochondrial proteins Seizures and Convulsions Effects on Mitochondrial Function 1) ACA/BHB oxidizes NADH 2) KB reduces ROS generation 3) protects against MRC inhibitors, elevates seizure threshold in patients with impaired MRC function 4) KD/KB elevates ATP production 5) Fatty acids activate mitochondrial uncouping proteins 6) KB elevates the threshold for mitochondrial permeability transition activation MPTp is a pore on the inner layer of the membrane How does ATP prevent seizures? Maintain ionic gradients through Na/K ATP pumps? No evidence for or against Lowered blood glucose levels Causes ATP release from cells Which is broken down into adenosine extracellularly Activates a1 receptors Open KATP Channels and hyperpolarizes cell Neuron is less excitable Effects of Decreased Glucose Metabolism 2DG, a glucose analog that inhibits glycolysis Anticonvulsant and antiepileptic Decreases synaptic transmission via adenosine Confounding findings about 2DG: GABAAR function Decreases BDNF and TrkB Anaplerosis Definition: process of replenishing Kreb s Cycle intermediates Seizures have been correlated to cause deficiencies in oxaloacetate and aketoglutarate Has been shown to oppose seizure generation Ketogenic Diet and Neuroprotection KD is not just helpful for epilepsy Ketogenic Diet and Neuroprotection KD is not just helpful for epilepsy...a prominent neuroprotective mechanism of KD action involves a reduction in mitochondrial free radical production, which would decrease oxidative stress, and potentially neuronal injury. Research in: Alzheimer s, Parkinson s, TBI, stroke, obesity, ALS, cancer!!! Thought to improve: lifespan, general mood, agerelated deficits in learning, motor coordination, weight Ketogenic Diet and Neuroprotection KD is not just helpful for epilepsy Ketone Bodies/PUFAs and Mitochondrial Function: Raise ATP levels in hippocampus Diminish ROS production ( NADH oxidation) Inhibit mitochondrial permeability More about ROSs: PUFAs UCP production reduced ROS production (and ATP synthesis, calcium influx into mitochondria, heat) UCP protects against kainateinduced excitotoxicity (probably by reducing ROS production) Discussion... It s becoming very apparent that the mechanisms are not simple. There have to be many mechanisms working in a coordinated fashion What is evident, however, is the increasing importance of studying neurometabolism. This research is important for epilepsy, but also for an expanding set of neurodegenerative diseases Conclusions... Conclusions
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