Excitotoxicity in ASDExcitotoxicity in ASD

Autism ONE ConferenceAutism ONE ConferenceMay 2008May 2008

Anju Usman, M. D.Anju Usman, M. D.True Health Medical CenterTrue Health Medical Center

Naperville, IllinoisNaperville, Illinois

Our kids carry the burdens Our kids carry the burdens of a physically and of a physically and emotionally toxic world!emotionally toxic world!

Genetic predispositionsGenetic predispositionsMother’s BurdensMother’s Burdens

Heavy MetalsHeavy MetalsEnvironmental PollutantsEnvironmental PollutantsElectromagnetic FieldsElectromagnetic FieldsExcess Sensory InputExcess Sensory Input

Stress/Internal ConflictsStress/Internal ConflictsDietary FactorsDietary Factors

Microbial/BiofilmMicrobial/BiofilmImmune/Inflammatory BurdenImmune/Inflammatory Burden

Metabolic Imprint of the Body BurdensMetabolic Imprint of the Body Burdens• Oxidative StressOxidative Stress

– Thimerosal (Mercury), Arsenic, Lead, Aluminum OverloadThimerosal (Mercury), Arsenic, Lead, Aluminum Overload– Depletion of Antioxidants, Glutathione, and MetallothioneinDepletion of Antioxidants, Glutathione, and Metallothionein

• Mitochondrial DysfunctionMitochondrial Dysfunction– Elevated Oxidative Stress MarkersElevated Oxidative Stress Markers– Abnormal Ammonia, Lactic Acid, Pyruvate AcidAbnormal Ammonia, Lactic Acid, Pyruvate Acid– Low CarnitineLow Carnitine

• Impaired DetoxificationImpaired Detoxification– Methylation DefectsMethylation Defects– Sulfation DefectsSulfation Defects– Cysteine Deficiency Cysteine Deficiency – Glutathione Deficiency (GSH)Glutathione Deficiency (GSH)

• Gastrointestinal DysfunctionGastrointestinal Dysfunction– Dysbiosis (Yeast, Bad Bacteria, Parasites, Virus…)Dysbiosis (Yeast, Bad Bacteria, Parasites, Virus…)– Malabsorption Malabsorption – Maldigestion (enzyme deficiency, IgG food sensitivities, urinary Maldigestion (enzyme deficiency, IgG food sensitivities, urinary

peptides)peptides)– Autistic Enterocolitis/ Lymphonodular HyperplasiaAutistic Enterocolitis/ Lymphonodular Hyperplasia

• Immune System Dysregulation/InflammationImmune System Dysregulation/Inflammation– Proinflammatory CytokinesProinflammatory Cytokines– Microglial ActivationMicroglial Activation– Th1/ Th2 skewingTh1/ Th2 skewing– Decreased Natural Killer Cell ActivityDecreased Natural Killer Cell Activity– Increased Autoimmune MarkersIncreased Autoimmune Markers

What exactly is causing my child’s What exactly is causing my child’s symptomssymptomsthat are being diagnosed as autism?that are being diagnosed as autism?

Verbal stims/ Perseverative/ Repetitive/ Has language but not Verbal stims/ Perseverative/ Repetitive/ Has language but not motivated to use it/ Rigid behaviors/ Scripted language/ motivated to use it/ Rigid behaviors/ Scripted language/

Constipated/Anxiety/OCD/ Motor TicsConstipated/Anxiety/OCD/ Motor Tics

Differential DiagnosisDifferential Diagnosis

Chronic InfectionsChronic InfectionsStrepStrep

VirusesVirusesGlutamate Glutamate AmmoniaAmmoniaMercuryMercury

AluminumAluminumLeadLead

PesticidesPesticidesVaccine Adjuvants (viral fragments)Vaccine Adjuvants (viral fragments)

All of these lead to Excitotoxicity in the brain!!!!All of these lead to Excitotoxicity in the brain!!!!

• ExcitotoxicityExcitotoxicity is the pathological process by which is the pathological process by which nerve cellsnerve cells are are damaged and killed by glutamate and similar substances. This occurs damaged and killed by glutamate and similar substances. This occurs when when receptorsreceptors for the excitatory neurotransmitter for the excitatory neurotransmitter glutamateglutamate such as the such as the NMDA receptorNMDA receptor and and AMPA receptorAMPA receptor are overactivated. Excitotoxins like are overactivated. Excitotoxins like NMDANMDA and and kainickainic acid acid which bind to these receptors, as well as which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of allowing high levels of calciumcalcium ions (Ca2+) to enter the ions (Ca2+) to enter the cellcell. Ca2+ influx . Ca2+ influx into cells activates a number of enzymes, including into cells activates a number of enzymes, including phospholipasesphospholipases, , endonucleasesendonucleases, and , and proteasesproteases such as such as calpaincalpain. These enzymes go on to . These enzymes go on to damage cell structures such as components of the damage cell structures such as components of the cytoskeletoncytoskeleton, , membranemembrane, and DNA., and DNA.

• The toxicity of glutamate was then observed by The toxicity of glutamate was then observed by D. R. LucasD. R. Lucas and J. P. and J. P. Newhouse in 1957 when the feeding of monosodium glutamate to newborn Newhouse in 1957 when the feeding of monosodium glutamate to newborn mice destroyed the neurons in the inner layers of the retina. Later, in 1969, mice destroyed the neurons in the inner layers of the retina. Later, in 1969, John Olney discovered the phenomenon wasn't restricted to the retina but John Olney discovered the phenomenon wasn't restricted to the retina but occurred throughout the brain and coined the term excitotoxicity. occurred throughout the brain and coined the term excitotoxicity.

• Excitotoxicity can occur from substances produced within the body Excitotoxicity can occur from substances produced within the body (endogenous (endogenous excitotoxinsexcitotoxins). Glutamate is a prime example of an excitotoxin ). Glutamate is a prime example of an excitotoxin in the brain, and it is paradoxically also the major excitatory in the brain, and it is paradoxically also the major excitatory neurotransmitter in the mammalian CNS.neurotransmitter in the mammalian CNS.

• One of the damaging results of excess calcium in the cytosol is the opening One of the damaging results of excess calcium in the cytosol is the opening of the mitochondrial permeability transitionof the mitochondrial permeability transition pore pore, a pore in the membranes , a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release proteins Opening of the pore may cause mitochondria to swell and release proteins that can lead to apoptosis. The pore can also cause mitochondria to that can lead to apoptosis. The pore can also cause mitochondria to release more calcium. release more calcium.

Excitotoxicity Excitotoxicity (Excess excitatory neurotransmission)(Excess excitatory neurotransmission)

– Causes brain atrophyCauses brain atrophy– Neuronal lossNeuronal loss– Brain more susceptible to ToxinsBrain more susceptible to Toxins– NeuroinflammationNeuroinflammation– Proinflammatory CytokinesProinflammatory Cytokines

• Increased TNF alphaIncreased TNF alpha• Increased IL-1, High IL-6Increased IL-1, High IL-6

– Upregulation of Brain Immune SystemUpregulation of Brain Immune System•Microglial ActivationMicroglial Activation

– ““Sickness Behavior” Sickness Behavior”

Russell Blaylock, “Vaccines, Neurodevelopment, and ASD”Russell Blaylock, “Vaccines, Neurodevelopment, and ASD”

Sickness BehaviorSickness Behavior

What does if feel like to be chronically What does if feel like to be chronically sick????sick????

RestlessRestlessIrritableIrritable

Disturbed SleepDisturbed SleepFatigueFatigue

Difficulty Thinking…Difficulty Thinking…

Russell Blaylock, “Vaccines, Depression and Neurodegeneration”Russell Blaylock, “Vaccines, Depression and Neurodegeneration”

Microglial ActivationMicroglial Activation

RESTING RESTING MICROGLIAMICROGLIA

• Support brain Support brain growthgrowth

• Protect brain cellsProtect brain cells

ACTIVATED MICROGLIAACTIVATED MICROGLIA• Ready to fight foreign Ready to fight foreign

invaderinvaderInflammatory cytokinesInflammatory cytokinesFree radicalsFree radicalsLipid PeroxidationLipid PeroxidationGlutamate productionGlutamate productionQuinolinic acidQuinolinic acid

  Autism and the Immune Autism and the Immune

systemsystem • It remains unclear how and when microglia and astroglia It remains unclear how and when microglia and astroglia

become activated in the brains of patients with autism. Glial become activated in the brains of patients with autism. Glial responses in autism may be part of intrinsic, or primary, responses in autism may be part of intrinsic, or primary, reactions that result from disturbances in glial function or reactions that result from disturbances in glial function or neuronal-glial interactions during brain development. They may neuronal-glial interactions during brain development. They may also be secondary, resulting from unknown disturbances (such also be secondary, resulting from unknown disturbances (such as infections or toxins) in prenatal or postnatal CNS as infections or toxins) in prenatal or postnatal CNS development. Nevertheless, the findings of this study highlight development. Nevertheless, the findings of this study highlight the existence of the existence of neuroimmunological processes in autismneuroimmunological processes in autism and and provide a setting for new research approaches to the diagnosis provide a setting for new research approaches to the diagnosis and treatment of this debilitating neurological disorder.and treatment of this debilitating neurological disorder.

• Slides A and C, from patients with autism, show an increase in Slides A and C, from patients with autism, show an increase in neuron-supporting cells called glia. This increase is likely a sign neuron-supporting cells called glia. This increase is likely a sign of a neuroimmunological response to the disorder. of a neuroimmunological response to the disorder. © 2005 Pardo et al.© 2005 Pardo et al.

Microglial Activation should Microglial Activation should only last a few days.only last a few days.

If insults persist….If insults persist….it can last yearsit can last years

Vaccine induced microglial activation, Vaccine induced microglial activation, especially when numerous vaccines are especially when numerous vaccines are given simultaneously, can last given simultaneously, can last YEARS.YEARS.

Russell Blaylock, “Vaccines, Depression and Russell Blaylock, “Vaccines, Depression and Neurodegeneration”Neurodegeneration”

Activated Immune SystemActivated Immune System

Infection/ToxinInfection/Toxin

CalciumCalciumGlutamate Glutamate AmmoniaAmmonia

InflammationInflammation

ImmuneImmuneActivationActivation

AcidosisAcidosis

Once the system is Once the system is turned on or turned on or activated the activated the cycle persists.cycle persists.

This persistent This persistent immune immune upregulation upregulation creates creates autoimmunity in autoimmunity in the body and the body and microglial microglial activation in the activation in the brain. brain.

The principle excitatory receptor, theThe principle excitatory receptor, the N-Methyl-D-Aspartate N-Methyl-D-Aspartate (NMDA) receptor, and its associated calcium (Ca2+) (NMDA) receptor, and its associated calcium (Ca2+) permeable ion channel are activated by glutamate and co-permeable ion channel are activated by glutamate and co-agonist glycine.agonist glycine.

Calcium HomeostasisCalcium Homeostasis• Calcium is one of the most important 2Calcium is one of the most important 2ndnd messengers messengers• Tightly regulated by stores, pumps and buffersTightly regulated by stores, pumps and buffers• VGCC- Voltage Gated Calcium ChannelsVGCC- Voltage Gated Calcium Channels

– L type (LTCC) L type (LTCC) • CNS CNS • Immune system Immune system • GI tractGI tract• Inner EarInner Ear

• Symptoms of abnormal Calcium homeostasisSymptoms of abnormal Calcium homeostasis– Excitation/Hyperactivity/Stimming BehaviorsExcitation/Hyperactivity/Stimming Behaviors– Muscle Tone /Coordination IssuesMuscle Tone /Coordination Issues– GI MotilityGI Motility– Visual DisturbancesVisual Disturbances– Auditory SensitivityAuditory Sensitivity– History of Kidney Stones, Fractures, Excess OxalatesHistory of Kidney Stones, Fractures, Excess Oxalates

““Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”ASD”

N.B.S. Lozac Feb. 2007N.B.S. Lozac Feb. 2007

Effects of Abnormal Calcium Effects of Abnormal Calcium

HomeostasisHomeostasis • NeurotransmittersNeurotransmitters– Decreased Nicotinic Acetylcholine, Increased Glutamate, Decreased DopamineDecreased Nicotinic Acetylcholine, Increased Glutamate, Decreased Dopamine

• Endocrine/HormoneEndocrine/Hormone– Impaired Insulin, Oxytocin, Vasopressin, Melatonin, Cortisol, IGF1Impaired Insulin, Oxytocin, Vasopressin, Melatonin, Cortisol, IGF1

• Immune/InflammatoryImmune/Inflammatory– Microglial activation, Th2 skewing, Proinflammatory cytokinesMicroglial activation, Th2 skewing, Proinflammatory cytokines– Viral induced immune suppressionViral induced immune suppression

• Vascular/Smooth MuscleVascular/Smooth Muscle• GastrointestinalGastrointestinal

– Increased Gastric Acid, Abnormal Motility, Increased Insulin release, Increased Gastric Acid, Abnormal Motility, Increased Insulin release, Phopholipase CPhopholipase C

• MembranesMembranes– Decreased Cholesterol Decreased Cholesterol

• MitochondriaMitochondria– Stores excess Calcium which inhibits Oxidative PhosphorylationStores excess Calcium which inhibits Oxidative Phosphorylation Poor Energy Poor Energy

Production and Elevation of ROS (reactive oxygen species)Production and Elevation of ROS (reactive oxygen species)

• Oxidative StressOxidative Stress– Cross Talk between Calcium and ROS(peroxide, nitrous oxide, superoxide) Cross Talk between Calcium and ROS(peroxide, nitrous oxide, superoxide) – Cause Damage to Endothelial CellsCause Damage to Endothelial Cells

• Motor – SensoryMotor – Sensory““Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”

N.B.S. Lozac Feb. 2007N.B.S. Lozac Feb. 2007

Potential Biomarkers of Potential Biomarkers of Abnormal Calcium HomeostasisAbnormal Calcium Homeostasis• Decreased Antioxidant StatusDecreased Antioxidant Status• Elevated Pro-oxidantsElevated Pro-oxidants• Elevated extracellular and intracellular Ca+2Elevated extracellular and intracellular Ca+2• Elevated ionized Calcium, elevated hair Ca+2Elevated ionized Calcium, elevated hair Ca+2• Elevated osteocalcinElevated osteocalcin• Elevated Alkaline Phosphatase (isoenzyme-Elevated Alkaline Phosphatase (isoenzyme-

bone)bone)• High CO2High CO2• Low Vitamin DLow Vitamin D• Elevated urinary oxalatesElevated urinary oxalates• HypoglycemiaHypoglycemia

Treating ExcitotoxicityTreating Excitotoxicity

1.1. Avoid Excitotoxins/Dietary ModificationsAvoid Excitotoxins/Dietary Modifications2.2. Use Glutamate ModulatorsUse Glutamate Modulators3.3. Maximize AntioxidantsMaximize Antioxidants4.4. Eliminate ToxinsEliminate Toxins5.5. Treat and Identify Chronic InfectionsTreat and Identify Chronic Infections6.6. Alkalinize the GutAlkalinize the Gut7.7. Limit excess Calcium, Ammonia, and GlutamateLimit excess Calcium, Ammonia, and Glutamate8.8. Support ATP production and the MitochondriaSupport ATP production and the Mitochondria9.9. Provide adequate Methylation supportProvide adequate Methylation support10.10.Natural Anti-InflammatoriesNatural Anti-Inflammatories

Avoid ExcitotoxinsAvoid Excitotoxins

Substances that Substances that cause an excess of cause an excess of excitatory excitatory neurotransmission in neurotransmission in the brain. The the brain. The excess excitation excess excitation may lead to may lead to microglial activation microglial activation and chronic and chronic inflammation in the inflammation in the brain.brain.

• Chronic InfectionsChronic Infections

• PesticidesPesticides

• Heavy MetalsHeavy Metals

• Glutamate/MSGGlutamate/MSG

• Sulfites/Hydrogen Sulfites/Hydrogen SulfideSulfide

• NitritesNitrites

• PropionatesPropionates

• BenzoatesBenzoates

Excitotoxic TriggersExcitotoxic Triggers

• GlutamateGlutamate– Monosodium Monosodium

Glutamate (MSG)Glutamate (MSG)– Hydrolyzed ProteinHydrolyzed Protein– Modified Food StarchModified Food Starch– Natural FlavorsNatural Flavors– Peas, Mushrooms, Peas, Mushrooms,

TomatoesTomatoes– Parmesan CheeseParmesan Cheese– Excess ProteinExcess Protein

• Excess CalciumExcess Calcium• Excess Excess

AmmoniaAmmonia• Excess Excess

Sulfur/Sulfite/Sulfur/Sulfite/ Hydrogen Hydrogen

SulfideSulfide• LeadLead• AluminumAluminum• MercuryMercury• EMFEMF

Glutamate ModulatorsGlutamate Modulators– MagnesiumMagnesium– AntioxidantsAntioxidants– Leucine, Isoleucine, and LysineLeucine, Isoleucine, and Lysine– PycnogenolPycnogenol– Rosemary, Lemon BalmRosemary, Lemon Balm– Skull Cap, ChamomileSkull Cap, Chamomile– TaurineTaurine– GABAGABA– L- TheanineL- Theanine– Vitamin KVitamin K– Gingko bilobaGingko biloba– SilymarinSilymarin– Flavinoids (curcumin, quercetin)Flavinoids (curcumin, quercetin)– Namenda (drug)Namenda (drug)– Minocycline (antibiotic)Minocycline (antibiotic)

Anti-oxidants Anti-oxidants • Excessive free radical formation/inadequate antioxidant status Excessive free radical formation/inadequate antioxidant status

is a major pathway of excitotoxic damage. is a major pathway of excitotoxic damage. • Various free radicals (ROS), including superoxide, peroxide, Various free radicals (ROS), including superoxide, peroxide,

hydroxyl and peroxynitrite, are generated through the hydroxyl and peroxynitrite, are generated through the inflammatory prostaglandin/leukotriene pathways triggered by inflammatory prostaglandin/leukotriene pathways triggered by excitotoxic intracellular calcium excess. excitotoxic intracellular calcium excess. 

• These free radicals can damage or destroy virtually every These free radicals can damage or destroy virtually every cellular biomolecule: proteins, fatty acids, phospholipids, cellular biomolecule: proteins, fatty acids, phospholipids, glycoproteins, even DNA, leading to cell injury or death.  glycoproteins, even DNA, leading to cell injury or death. 

• Although Although vitamins Cvitamins C and and EE are the two most important are the two most important nutritional antioxidants. Brain cells may concentrate C to nutritional antioxidants. Brain cells may concentrate C to levels 100 times higher than blood levels. levels 100 times higher than blood levels. 

• Vitamin C, E, alpha-lipoic acid, Co Q10Vitamin C, E, alpha-lipoic acid, Co Q10 and and NADHNADH act as a act as a team.team.

• One of the many ways excitotoxins damage neurons is to One of the many ways excitotoxins damage neurons is to prevent the intracellular formation of prevent the intracellular formation of glutathioneglutathione. .

• The combination of E and The combination of E and Idebenone Idebenone may provided complete may provided complete antioxidant neuronal protection in spite of extremely low antioxidant neuronal protection in spite of extremely low glutathione levels caused by glutamate excitotoxic action.glutathione levels caused by glutamate excitotoxic action.

   

Antioxidant PhytonutrientsAntioxidant Phytonutrients

Infections produce triggers that Infections produce triggers that cause excitotoxicity!cause excitotoxicity!• VirusesViruses• Bacteria- especially Strep and Clostridia………..Bacteria- especially Strep and Clostridia………..• YeastYeast• ParasitesParasites• LymeLyme• MycoplasmaMycoplasma

Chronic infections need to be effectively treated to stop Chronic infections need to be effectively treated to stop persistent activation of the immune system.persistent activation of the immune system.

Infections are common in ASD patients. These infections are often Infections are common in ASD patients. These infections are often resistant to treatment. Persistent organisms often produce resistant to treatment. Persistent organisms often produce biofilm.biofilm.

Toxic Foci include tonsils, adenoids, ears, lymph nodes, GI tract…Toxic Foci include tonsils, adenoids, ears, lymph nodes, GI tract…

Some infections produce excess ammonia.Some infections produce excess ammonia.

Keys to treating chronic Keys to treating chronic infectionsinfections

• Identify type and locationIdentify type and location• Aggressively clean up the gutAggressively clean up the gut• Breakdown biofilm (diet, nutrition, and Breakdown biofilm (diet, nutrition, and

alkalinize)alkalinize)• Treat infections with homeopathics and Treat infections with homeopathics and

natural agents if possible natural agents if possible • Be patient Be patient • Keep ammonia levels low Keep ammonia levels low • Have a plan to manage die offHave a plan to manage die off

AmmoniaAmmonia• If severely elevated rule out urea cycle If severely elevated rule out urea cycle

disorderdisorder• If mildly elevated consider possible causesIf mildly elevated consider possible causes

– DysbiosisDysbiosis– Recent infectionRecent infection– Liver stressLiver stress– High protein diet or supplementsHigh protein diet or supplements– BH4 (tetrahydrobiopterin deficiency)BH4 (tetrahydrobiopterin deficiency)

• SymptomsSymptoms– Irritability, aggression, headache, head-banging, Irritability, aggression, headache, head-banging,

hyperactivityhyperactivity

• Treatment StrategiesTreatment Strategies– Avoid excess protein in dietAvoid excess protein in diet– Activated Charcoal, Fiber, Pectin, ZeolitesActivated Charcoal, Fiber, Pectin, Zeolites– Yucca / AloeYucca / Aloe– BH4BH4– Butyrate Butyrate – Ammonia RNA (Yasko)Ammonia RNA (Yasko)

Vitamin K Protocol Vitamin K Protocol (Catherine (Catherine Tamaro)Tamaro)

• Vit KVit K• Vit DVit D• Vit AVit A• DHADHA• BicarbonateBicarbonate• MelatoninMelatonin• Avoid Calcium supplementationAvoid Calcium supplementation

This Protocol is good for addressingThis Protocol is good for addressing excess extracellular calcium.excess extracellular calcium.

The Mitochondria is theThe Mitochondria is thepowerhouse of each cell.powerhouse of each cell.

Inside the Mitochondria, Inside the Mitochondria, the Citric Acid Cyclethe Citric Acid Cycleproduces ATP.produces ATP.

ATP is the fuel for the ATP is the fuel for the cell.cell.

ATP provides energy.ATP provides energy.

ATP (adenosine ATP (adenosine triphosphate)triphosphate)

• ATP is the energy "currency" of all cells, including neurons.  ATP is the energy "currency" of all cells, including neurons.  Each neuron must produce all the ATP it needs - there is no Each neuron must produce all the ATP it needs - there is no welfare state to take care of needy but helpless neurons.  welfare state to take care of needy but helpless neurons. 

• ATP is needed to pump glutamate out of the synaptic gap into ATP is needed to pump glutamate out of the synaptic gap into either the glutamate-secreting neuron or into astrocytes.  either the glutamate-secreting neuron or into astrocytes.  ATP ATP is needed by atrocytes to convert glutamate into glutamineis needed by atrocytes to convert glutamate into glutamine.  . 

• ATP is needed by sodium and calcium pumps to get excess ATP is needed by sodium and calcium pumps to get excess sodium and calcium back out of the neuron after neuron sodium and calcium back out of the neuron after neuron firing.firing. ATP is needed to maintain neuron resting electric ATP is needed to maintain neuron resting electric potential, which in turn maintains the magnesium-block of the potential, which in turn maintains the magnesium-block of the glutamate-NMDA receptor.  With enough ATP bioenergy, glutamate-NMDA receptor.  With enough ATP bioenergy, neurons can keep glutamate and aspartate in their proper role neurons can keep glutamate and aspartate in their proper role as neurotransmitters. as neurotransmitters.

• Neurons produce ATP by "burning" glucose (blood sugar) Neurons produce ATP by "burning" glucose (blood sugar) through 3 interlocking cellular cycles: the glycolytic and Krebs' through 3 interlocking cellular cycles: the glycolytic and Krebs' cycles, and the electron transport chain, with most of the ATP cycles, and the electron transport chain, with most of the ATP coming from the electron transport chain.coming from the electron transport chain.

• Various enzyme assemblies produce ATP from glucose through Various enzyme assemblies produce ATP from glucose through these 3 cycles, with the Krebs' cycle and electron transport these 3 cycles, with the Krebs' cycle and electron transport chain occurring inside mitochondria, the power plants of the chain occurring inside mitochondria, the power plants of the cell.cell.

Mitochondrial Support and ATP Mitochondrial Support and ATP ProductionProduction• The various enzyme assemblies require vitamins The various enzyme assemblies require vitamins B1, B2, B3 B1, B2, B3

(NADH), B5, biotin, and alpha-lipoic acid(NADH), B5, biotin, and alpha-lipoic acid as coenzymes.  as coenzymes.  • MagnesiumMagnesium is also required by most of the glycolytic and is also required by most of the glycolytic and

Krebs' cycle enzymes as a mineral co-factor.Krebs' cycle enzymes as a mineral co-factor.• The electron transport chain especially relies on NADH and The electron transport chain especially relies on NADH and

Co Q10Co Q10 to generate the bulk of the cell's ATP.  to generate the bulk of the cell's ATP.  • IdebenoneIdebenone is a synthetic variant of Co Q10 that may work is a synthetic variant of Co Q10 that may work

better than CoQ10, especially in low oxygen conditions, to better than CoQ10, especially in low oxygen conditions, to keep ATP production going in the electron transport chain.  keep ATP production going in the electron transport chain. 

• Acetyl l-carnitineAcetyl l-carnitine may regenerate aging mitochondria that may regenerate aging mitochondria that are suffering from a lifetime of accumulated free radical are suffering from a lifetime of accumulated free radical damage.damage.

• Potential Krebs Cycle Support Potential Krebs Cycle Support – Malic AcidMalic Acid– Fumaric AcidFumaric Acid– Succinic AcidSuccinic Acid– Alpha Keto Glutarate (careful)Alpha Keto Glutarate (careful)

Amy Amy Yasko Yasko Diagram (2005)Diagram (2005)

Text

Methylation & Beyond...

Methylation Support and Glutathione Methylation Support and Glutathione ProductionProduction• Combination of Pfeiffer Treatment Center, Combination of Pfeiffer Treatment Center,

Defeat Autism Now, and Yasko ApproachDefeat Autism Now, and Yasko Approach• Understanding the underlying genetics is Understanding the underlying genetics is

helpful in difficult caseshelpful in difficult cases• CBS status, MTHFR, MTR, MTRR and COMT are CBS status, MTHFR, MTR, MTRR and COMT are

helpful for understanding methylation issueshelpful for understanding methylation issues• Amino Acid testing and Cysteine, Glutathione, Amino Acid testing and Cysteine, Glutathione,

and Sulfate levels define picture.and Sulfate levels define picture.• Undermethylation, COMT (- -), High HistamineUndermethylation, COMT (- -), High Histamine• Overmethylation, COMT (++), Low HistamineOvermethylation, COMT (++), Low Histamine

COMT - - Treatment COMT - - Treatment approachapproach

DANDANMethyl B12Methyl B12

TMGTMG

DMGDMG

P5PP5P

Folinic AcidFolinic Acid

CreatineCreatine

L CarnitineL Carnitine

Glutathione(GSH)Glutathione(GSH)

YaskoYaskoIntrinsic B12Intrinsic B12

NucleotidesNucleotides

MethylfolateMethylfolate

BH4BH4

GSH(limited)GSH(limited)

Emphasis on Emphasis on

Methyl Donors:Methyl Donors:Methyl B12Methyl B12

SAMeSAMe

QuercetinQuercetin

GingkoGingko

CurcuminCurcumin

Green TeaGreen Tea

Phosphatidyl SerinePhosphatidyl Serine

PfeifferPfeifferMethionine/SAMeMethionine/SAMe

Methyl B12Methyl B12

CalciumCalcium

MagnesiumMagnesium

P5P/B6P5P/B6

ZincZinc

Vitamin CVitamin C

Phosphatidyl SerinePhosphatidyl SerineAvoid Methyl Avoid Methyl

Consumers:Consumers:FolatesFolates

DMAEDMAE

Cyano B12Cyano B12

NiacinamideNiacinamide

COMT + + Treatment COMT + + Treatment approachapproach

DANDANMethyl B12Methyl B12

TMGTMG

DMGDMG

P5PP5P

Folinic AcidFolinic Acid

CreatineCreatine

L CarnitineL Carnitine

GlutathioneGlutathione

YaskoYaskoIntrinsic B12Intrinsic B12

NucleotidesNucleotides

MethylfolateMethylfolate

Hydroxy B12Hydroxy B12

Cyano B12Cyano B12

BH4BH4Limit Methyl Donors:Limit Methyl Donors:

Methyl B12Methyl B12

QuercetinQuercetin

GingkoGingko

CurcuminCurcumin

Green TeaGreen Tea

Phosphatidyl SerinePhosphatidyl Serine

PfeifferPfeifferFolic AcidFolic Acid

Cyano B12Cyano B12

NiacinamideNiacinamide

P5P, Vit B6P5P, Vit B6

Zinc, Mb, MnZinc, Mb, Mn

Vitamin CVitamin C

DMAE/Phosphatidyl DMAE/Phosphatidyl CholineCholine

Avoid Methyl Donors:Avoid Methyl Donors:Methyl B12Methyl B12

Methyl FolateMethyl Folate

MethionineMethionine

SAMeSAMe

Natural Anti-inflammatory AgentsNatural Anti-inflammatory Agents

• The excitotoxic process does much of its damage through The excitotoxic process does much of its damage through initiating excessive production of prostaglandins, initiating excessive production of prostaglandins, thromboxanes, and leukotrienes. thromboxanes, and leukotrienes.

• Inflammatory prostaglandins and thromboxanes are Inflammatory prostaglandins and thromboxanes are produced by the action of cyclooxygenase 2 (COX-2) on produced by the action of cyclooxygenase 2 (COX-2) on arachidonic acid liberated from cell membranes   arachidonic acid liberated from cell membranes   Leukotrienes are produced by lipoxygenases (LOX).  Leukotrienes are produced by lipoxygenases (LOX). 

• Trans-resveratrol Trans-resveratrol is a powerful natural inhibitor of both COX-is a powerful natural inhibitor of both COX-2 and LOX 2 and LOX

• Quercetin Quercetin is a powerful LOX-inhibitor.is a powerful LOX-inhibitor.• BoswelliaBoswellia is a COX-2 and LOX-inhibitor. is a COX-2 and LOX-inhibitor.• Curcumin Curcumin (turmeric extract), rosemary extract, green tea (turmeric extract), rosemary extract, green tea

extract, ginger and oregano are also effective natural COX-2 extract, ginger and oregano are also effective natural COX-2 inhibitors. inhibitors. 

• GlutathioneGlutathione is also a LOX- inhibitor and potent Antioxidant. is also a LOX- inhibitor and potent Antioxidant.• AntioxidantsAntioxidants have anti-inflammatory effects. have anti-inflammatory effects.• Fat Soluble Vitamins A,D,E, and K.Fat Soluble Vitamins A,D,E, and K.• Essential Fatty Acids, Essential Fatty Acids, Omega 3Omega 3 especially DHA. especially DHA.

Keys to Excess Glutamate Keys to Excess Glutamate RemovalRemoval

• Avoid dietary Excitotoxins will help to minimize synaptic Avoid dietary Excitotoxins will help to minimize synaptic glutamate/aspartate.glutamate/aspartate.

• Keep neuronal ATP energy maximal by support of the Mitochondria Keep neuronal ATP energy maximal by support of the Mitochondria – Avoidance of hypoglycemia Avoidance of hypoglycemia – ATP Production will assist glutamate pumps to remove excess extracellular ATP Production will assist glutamate pumps to remove excess extracellular

glutamate  glutamate  – ATP promotes astrocyte conversion of glutamate to glutamine, the chief ATP promotes astrocyte conversion of glutamate to glutamine, the chief

glutamate removal mechanism. glutamate removal mechanism. – ATP will also keep calcium and sodium pumps active, preventing excessive ATP will also keep calcium and sodium pumps active, preventing excessive

intracellular calcium build-up. Intracellular calcium excess itself promotes intracellular calcium build-up. Intracellular calcium excess itself promotes renewed secretion of glutamate into synapses, in a positive feedback vicious renewed secretion of glutamate into synapses, in a positive feedback vicious cycle.cycle.

    • Maintain function of the enzyme "glutamatic acid dehydrogenase (GAD)" Maintain function of the enzyme "glutamatic acid dehydrogenase (GAD)"

– Helps neurons dispose of excess glutamate by converting glutamate to alpha-Helps neurons dispose of excess glutamate by converting glutamate to alpha-ketoglutarate, a Krebs' cycle fuel.ketoglutarate, a Krebs' cycle fuel.

– Glutamate dehydrogenase is activated by NADH, it promotes breakdown of Glutamate dehydrogenase is activated by NADH, it promotes breakdown of glutamate.glutamate.

– Treat toxins that inhibit GAD, like aluminum, lead, mercury, and pesticides…Treat toxins that inhibit GAD, like aluminum, lead, mercury, and pesticides…

• Consume plenty of antioxidants which aid in removal of synaptic Consume plenty of antioxidants which aid in removal of synaptic glutamate.  glutamate.  – Avoid use of glutamine.  Glutamine easily passes the blood-brain barrier and Avoid use of glutamine.  Glutamine easily passes the blood-brain barrier and

enters the astrocytes and neurons, where it can be converted to glutamate. enters the astrocytes and neurons, where it can be converted to glutamate. 

p5p

Succinic Acid

Krebs/Mitochondria

GABA

Amino acidsp5p

Proline Decarboxylase

(brain, kidney) p5p

NADNADP

NADHNADPH

AKG

Krebs/Mitochondria

Glutamic acid dehydrogenase

Mg

ADP

ATP

Glutamine

Glutamic Acid

NH3/ Ammonia

GABA/Glutamate CycleGABA/Glutamate Cycle

Additional Sources of Additional Sources of InformationInformation

• Healing the New Childhood Epidemics (Autism, ADHD, Healing the New Childhood Epidemics (Autism, ADHD, Asthma and Asthma and Allergies, Ken Bock MDAllergies, Ken Bock MD

• Autism: Effective Biomedical TreatmentsAutism: Effective Biomedical Treatments, Pangborn , Pangborn and Baker and Baker

• Changing the Course of Autism, Changing the Course of Autism, Jepson and JohnsonJepson and Johnson• Excitotoxins, the Taste that KillsExcitotoxins, the Taste that Kills, Russell Blaylock MD, Russell Blaylock MD• Envisioning a Brighter FutureEnvisioning a Brighter Future, Patty Lemur, Patty Lemur• WebsitesWebsites

– www.autism.comwww.autism.com– www.safeminds.orgwww.safeminds.org – www.autismone.orgwww.autismone.org– www.generationrescue.orgwww.generationrescue.org – www.vaccineawareness.orgwww.vaccineawareness.org– www.ddr.orgwww.ddr.org

Thank You Thank You and Never Give Up Hope.and Never Give Up Hope.