Presentation on theme: "True Health Medical Center"— Presentation transcript:
1True Health Medical Center Excitotoxicity in ASDAutism ONE ConferenceMay 2008Anju Usman, M. D.True Health Medical CenterNaperville, Illinois
2Our kids carry the burdens of a physically and emotionally toxic world! Genetic predispositionsMother’s BurdensHeavy MetalsEnvironmental PollutantsElectromagnetic FieldsExcess Sensory InputStress/Internal ConflictsDietary FactorsMicrobial/BiofilmImmune/Inflammatory Burden
3Metabolic Imprint of the Body Burdens Oxidative StressThimerosal (Mercury), Arsenic, Lead, Aluminum OverloadDepletion of Antioxidants, Glutathione, and MetallothioneinMitochondrial DysfunctionElevated Oxidative Stress MarkersAbnormal Ammonia, Lactic Acid, Pyruvate AcidLow CarnitineImpaired DetoxificationMethylation DefectsSulfation DefectsCysteine DeficiencyGlutathione Deficiency (GSH)Gastrointestinal DysfunctionDysbiosis (Yeast, Bad Bacteria, Parasites, Virus…)MalabsorptionMaldigestion (enzyme deficiency, IgG food sensitivities, urinary peptides)Autistic Enterocolitis/ Lymphonodular HyperplasiaImmune System Dysregulation/InflammationProinflammatory CytokinesMicroglial ActivationTh1/ Th2 skewingDecreased Natural Killer Cell ActivityIncreased Autoimmune Markers
4What exactly is causing my child’s symptoms that are being diagnosed as autism? Verbal stims/ Perseverative/ Repetitive/ Has language but not motivated to use it/ Rigid behaviors/ Scripted language/ Constipated/Anxiety/OCD/ Motor TicsDifferential DiagnosisChronic InfectionsStrepVirusesGlutamateAmmoniaMercuryAluminumLeadPesticidesVaccine Adjuvants (viral fragments)All of these lead to Excitotoxicity in the brain!!!!
5Excitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.The toxicity of glutamate was then observed by D. R. Lucas and J. P. 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, John Olney discovered the phenomenon wasn't restricted to the retina but occurred throughout the brain and coined the term excitotoxicity.Excitotoxicity can occur from substances produced within the body (endogenous excitotoxins). Glutamate is a prime example of an excitotoxin in the brain, and it is paradoxically also the major excitatory neurotransmitter in the mammalian CNS.One of the damaging results of excess calcium in the cytosol is the opening of the mitochondrial permeability transition pore, a pore in the membranes of mitochondria that opens when the organelles absorb too much calcium. Opening of the pore may cause mitochondria to swell and release proteins that can lead to apoptosis. The pore can also cause mitochondria to release more calcium.
6Excitotoxicity (Excess excitatory neurotransmission) Causes brain atrophyNeuronal lossBrain more susceptible to ToxinsNeuroinflammationProinflammatory CytokinesIncreased TNF alphaIncreased IL-1, High IL-6Upregulation of Brain Immune SystemMicroglial Activation“Sickness Behavior”Russell Blaylock, “Vaccines, Neurodevelopment, and ASD”
7Sickness Behavior What does if feel like to be chronically sick???? RestlessIrritableDisturbed SleepFatigueDifficulty Thinking…Russell Blaylock, “Vaccines, Depression and Neurodegeneration”
10Russell Blaylock, “Vaccines, Depression and Neurodegeneration” Microglial Activation should only last a few days. If insults persist…. it can last yearsVaccine induced microglial activation, especially when numerous vaccines are given simultaneously, can last YEARS.Russell Blaylock, “Vaccines, Depression and Neurodegeneration”
11Activated Immune System Once the system is turned on or activated the cycle persists.This persistent immune upregulation creates autoimmunity in the body and microglial activation in the brain.
12Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols The principle excitatory receptor, the N-Methyl-D-Aspartate (NMDA) receptor, and its associated calcium (Ca2+) permeable ion channel are activated by glutamate and co-agonist glycine.
13Calcium Homeostasis Symptoms of abnormal Calcium homeostasis Calcium is one of the most important 2nd messengersTightly regulated by stores, pumps and buffersVGCC- Voltage Gated Calcium ChannelsL type (LTCC)CNSImmune systemGI tractInner EarSymptoms of abnormal Calcium homeostasisExcitation/Hyperactivity/Stimming BehaviorsMuscle Tone /Coordination IssuesGI MotilityVisual DisturbancesAuditory SensitivityHistory of Kidney Stones, Fractures, Excess Oxalates“Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”N.B.S. Lozac Feb. 2007
14Effects of Abnormal Calcium Homeostasis NeurotransmittersDecreased Nicotinic Acetylcholine, Increased Glutamate, Decreased DopamineEndocrine/HormoneImpaired Insulin, Oxytocin, Vasopressin, Melatonin, Cortisol, IGF1Immune/InflammatoryMicroglial activation, Th2 skewing, Proinflammatory cytokinesViral induced immune suppressionVascular/Smooth MuscleGastrointestinalIncreased Gastric Acid, Abnormal Motility, Increased Insulin release, Phopholipase CMembranesDecreased CholesterolMitochondriaStores excess Calcium which inhibits Oxidative Phosphorylation Poor Energy Production and Elevation of ROS (reactive oxygen species)Oxidative StressCross Talk between Calcium and ROS(peroxide, nitrous oxide, superoxide)Cause Damage to Endothelial CellsMotor – Sensory“Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD”N.B.S. Lozac Feb. 2007
16Treating Excitotoxicity Avoid Excitotoxins/Dietary ModificationsUse Glutamate ModulatorsMaximize AntioxidantsEliminate ToxinsTreat and Identify Chronic InfectionsAlkalinize the GutLimit excess Calcium, Ammonia, and GlutamateSupport ATP production and the MitochondriaProvide adequate Methylation supportNatural Anti-Inflammatories
17Avoid ExcitotoxinsSubstances that cause an excess of excitatory neurotransmission in the brain. The excess excitation may lead to microglial activation and chronic inflammation in the brain.Chronic InfectionsPesticidesHeavy MetalsGlutamate/MSGSulfites/Hydrogen SulfideNitritesPropionatesBenzoates
19Glutamate Modulators Magnesium Antioxidants Fine Tuning Detoxification Strategies and Individualizing Chelation ProtocolsGlutamate ModulatorsMagnesiumAntioxidantsLeucine, Isoleucine, and LysinePycnogenolRosemary, Lemon BalmSkull Cap, ChamomileTaurineGABAL- TheanineVitamin KGingko bilobaSilymarinFlavinoids (curcumin, quercetin)Namenda (drug)Minocycline (antibiotic)
20Anti-oxidantsExcessive free radical formation/inadequate antioxidant status is a major pathway of excitotoxic damage. Various free radicals (ROS), including superoxide, peroxide, hydroxyl and peroxynitrite, are generated through the inflammatory prostaglandin/leukotriene pathways triggered by excitotoxic intracellular calcium excess. These free radicals can damage or destroy virtually every cellular biomolecule: proteins, fatty acids, phospholipids, glycoproteins, even DNA, leading to cell injury or death. Although vitamins C and E are the two most important nutritional antioxidants. Brain cells may concentrate C to levels 100 times higher than blood levels. Vitamin C, E, alpha-lipoic acid, Co Q10 and NADH act as a team.One of the many ways excitotoxins damage neurons is to prevent the intracellular formation of glutathione.The combination of E and Idebenone may provided complete antioxidant neuronal protection in spite of extremely low glutathione levels caused by glutamate excitotoxic action.
22Infections produce triggers that cause excitotoxicity! Fine Tuning Detoxification Strategies and Individualizing Chelation ProtocolsInfections produce triggers that cause excitotoxicity!VirusesBacteria- especially Strep and Clostridia………..YeastParasitesLymeMycoplasmaChronic infections need to be effectively treated to stop persistent activation of the immune system.Infections are common in ASD patients. These infections are often resistant to treatment. Persistent organisms often produce biofilm.Toxic Foci include tonsils, adenoids, ears, lymph nodes, GI tract…Some infections produce excess ammonia.
23Keys to treating chronic infections Identify type and locationAggressively clean up the gutBreakdown biofilm (diet, nutrition, and alkalinize)Treat infections with homeopathics and natural agents if possibleBe patientKeep ammonia levels lowHave a plan to manage die off
24Ammonia If severely elevated rule out urea cycle disorder Fine Tuning Detoxification Strategies and Individualizing Chelation ProtocolsIf severely elevated rule out urea cycle disorderIf mildly elevated consider possible causesDysbiosisRecent infectionLiver stressHigh protein diet or supplementsBH4 (tetrahydrobiopterin deficiency)SymptomsIrritability, aggression, headache, head-banging, hyperactivityTreatment StrategiesAvoid excess protein in dietActivated Charcoal, Fiber, Pectin, ZeolitesYucca / AloeBH4ButyrateAmmonia RNA (Yasko)
25Vitamin K Protocol (Catherine Tamaro) Vit KVit DVit ADHABicarbonateMelatoninAvoid Calcium supplementationThis Protocol is good for addressingexcess extracellular calcium.
26The Mitochondria is the powerhouse of each cell.Inside the Mitochondria,the Citric Acid Cycleproduces ATP.ATP is the fuel for the cell.ATP provides energy.
27ATP (adenosine triphosphate) ATP is the energy "currency" of all cells, including neurons. Each neuron must produce all the ATP it needs - there is no welfare state to take care of needy but helpless neurons. ATP is needed to pump glutamate out of the synaptic gap into either the glutamate-secreting neuron or into astrocytes. ATP is needed by atrocytes to convert glutamate into glutamine. ATP is needed by sodium and calcium pumps to get excess sodium and calcium back out of the neuron after neuron firing. ATP is needed to maintain neuron resting electric potential, which in turn maintains the magnesium-block of the glutamate-NMDA receptor. With enough ATP bioenergy, neurons can keep glutamate and aspartate in their proper role as neurotransmitters.Neurons produce ATP by "burning" glucose (blood sugar) through 3 interlocking cellular cycles: the glycolytic and Krebs' cycles, and the electron transport chain, with most of the ATP coming from the electron transport chain.Various enzyme assemblies produce ATP from glucose through these 3 cycles, with the Krebs' cycle and electron transport chain occurring inside mitochondria, the power plants of the cell.
28Mitochondrial Support and ATP Production The various enzyme assemblies require vitamins B1, B2, B3 (NADH), B5, biotin, and alpha-lipoic acid as coenzymes. Magnesium is also required by most of the glycolytic and Krebs' cycle enzymes as a mineral co-factor.The electron transport chain especially relies on NADH and Co Q10 to generate the bulk of the cell's ATP. Idebenone is a synthetic variant of Co Q10 that may work better than CoQ10, especially in low oxygen conditions, to keep ATP production going in the electron transport chain. Acetyl l-carnitine may regenerate aging mitochondria that are suffering from a lifetime of accumulated free radical damage.Potential Krebs Cycle Support Malic AcidFumaric AcidSuccinic AcidAlpha Keto Glutarate (careful)
30Methylation Support and Glutathione Production Combination of Pfeiffer Treatment Center, Defeat Autism Now, and Yasko ApproachUnderstanding the underlying genetics is helpful in difficult casesCBS status, MTHFR, MTR, MTRR and COMT are helpful for understanding methylation issuesAmino Acid testing and Cysteine, Glutathione, and Sulfate levels define picture.Undermethylation, COMT (- -), High HistamineOvermethylation, COMT (++), Low Histamine
33Natural Anti-inflammatory Agents The excitotoxic process does much of its damage through initiating excessive production of prostaglandins, thromboxanes, and leukotrienes.Inflammatory prostaglandins and thromboxanes are produced by the action of cyclooxygenase 2 (COX-2) on arachidonic acid liberated from cell membranes Leukotrienes are produced by lipoxygenases (LOX). Trans-resveratrol is a powerful natural inhibitor of both COX-2 and LOXQuercetin is a powerful LOX-inhibitor.Boswellia is a COX-2 and LOX-inhibitor.Curcumin (turmeric extract), rosemary extract, green tea extract, ginger and oregano are also effective natural COX-2 inhibitors. Glutathione is also a LOX- inhibitor and potent Antioxidant.Antioxidants have anti-inflammatory effects.Fat Soluble Vitamins A,D,E, and K.Essential Fatty Acids, Omega 3 especially DHA.
34Keys to Excess Glutamate Removal Avoid dietary Excitotoxins will help to minimize synaptic glutamate/aspartate.Keep neuronal ATP energy maximal by support of the MitochondriaAvoidance of hypoglycemiaATP Production will assist glutamate pumps to remove excess extracellular glutamate ATP promotes astrocyte conversion of glutamate to glutamine, the chief glutamate removal mechanism. ATP will also keep calcium and sodium pumps active, preventing excessive intracellular calcium build-up. Intracellular calcium excess itself promotes renewed secretion of glutamate into synapses, in a positive feedback vicious cycle.Maintain function of the enzyme "glutamatic acid dehydrogenase (GAD)"Helps neurons dispose of excess glutamate by converting glutamate to alpha-ketoglutarate, a Krebs' cycle fuel.Glutamate dehydrogenase is activated by NADH, it promotes breakdown of glutamate.Treat toxins that inhibit GAD, like aluminum, lead, mercury, and pesticides…Consume plenty of antioxidants which aid in removal of synaptic glutamate. Avoid use of glutamine. Glutamine easily passes the blood-brain barrier and enters the astrocytes and neurons, where it can be converted to glutamate.
36Additional Sources of Information Fine Tuning Detoxification Strategies and Individualizing Chelation ProtocolsAdditional Sources of InformationHealing the New Childhood Epidemics (Autism, ADHD, Asthma and Allergies, Ken Bock MDAutism: Effective Biomedical Treatments, Pangborn and BakerChanging the Course of Autism, Jepson and JohnsonExcitotoxins, the Taste that Kills, Russell Blaylock MDEnvisioning a Brighter Future, Patty LemurWebsites
37Thank You and Never Give Up Hope. Fine Tuning Detoxification Strategies and Individualizing Chelation ProtocolsThank You and Never Give Up Hope.