True Health Medical Center Excitotoxicity in ASD Autism ONE Conference May 2008 Anju Usman, M. D. True Health Medical Center Naperville, Illinois

Our kids carry the burdens of a physically and emotionally toxic world! Genetic predispositions Mother’s Burdens Heavy Metals Environmental Pollutants Electromagnetic Fields Excess Sensory Input Stress/Internal Conflicts Dietary Factors Microbial/Biofilm Immune/Inflammatory Burden

Metabolic Imprint of the Body Burdens Oxidative Stress Thimerosal (Mercury), Arsenic, Lead, Aluminum Overload Depletion of Antioxidants, Glutathione, and Metallothionein Mitochondrial Dysfunction Elevated Oxidative Stress Markers Abnormal Ammonia, Lactic Acid, Pyruvate Acid Low Carnitine Impaired Detoxification Methylation Defects Sulfation Defects Cysteine Deficiency Glutathione Deficiency (GSH) Gastrointestinal Dysfunction Dysbiosis (Yeast, Bad Bacteria, Parasites, Virus…) Malabsorption Maldigestion (enzyme deficiency, IgG food sensitivities, urinary peptides) Autistic Enterocolitis/ Lymphonodular Hyperplasia Immune System Dysregulation/Inflammation Proinflammatory Cytokines Microglial Activation Th1/ Th2 skewing Decreased Natural Killer Cell Activity Increased Autoimmune Markers

What 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 Tics Differential Diagnosis Chronic Infections Strep Viruses Glutamate Ammonia Mercury Aluminum Lead Pesticides Vaccine Adjuvants (viral fragments) All of these lead to Excitotoxicity in the brain!!!!

Excitotoxicity 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.

Excitotoxicity (Excess excitatory neurotransmission) Causes brain atrophy Neuronal loss Brain more susceptible to Toxins Neuroinflammation Proinflammatory Cytokines Increased TNF alpha Increased IL-1, High IL-6 Upregulation of Brain Immune System Microglial Activation “Sickness Behavior” Russell Blaylock, “Vaccines, Neurodevelopment, and ASD”

Sickness Behavior What does if feel like to be chronically sick???? Restless Irritable Disturbed Sleep Fatigue Difficulty Thinking… Russell Blaylock, “Vaccines, Depression and Neurodegeneration”

Microglial Activation RESTING MICROGLIA Support brain growth Protect brain cells ACTIVATED MICROGLIA Ready to fight foreign invader Inflammatory cytokines Free radicals Lipid Peroxidation Glutamate production Quinolinic acid

Autism and the Immune system It remains unclear how and when microglia and astroglia become activated in the brains of patients with autism. Glial responses in autism may be part of intrinsic, or primary, reactions that result from disturbances in glial function or neuronal-glial interactions during brain development. They may also be secondary, resulting from unknown disturbances (such as infections or toxins) in prenatal or postnatal CNS development. Nevertheless, the findings of this study highlight the existence of neuroimmunological processes in autism and provide a setting for new research approaches to the diagnosis and treatment of this debilitating neurological disorder. Slides A and C, from patients with autism, show an increase in neuron-supporting cells called glia. This increase is likely a sign of a neuroimmunological response to the disorder. © 2005 Pardo et al.

Russell Blaylock, “Vaccines, Depression and Neurodegeneration” Microglial Activation should only last a few days. If insults persist…. it can last years Vaccine induced microglial activation, especially when numerous vaccines are given simultaneously, can last YEARS. Russell Blaylock, “Vaccines, Depression and Neurodegeneration”

Activated 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.

Fine 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.

Calcium Homeostasis Symptoms of abnormal Calcium homeostasis Calcium is one of the most important 2nd messengers Tightly regulated by stores, pumps and buffers VGCC- Voltage Gated Calcium Channels L type (LTCC) CNS Immune system GI tract Inner Ear Symptoms of abnormal Calcium homeostasis Excitation/Hyperactivity/Stimming Behaviors Muscle Tone /Coordination Issues GI Motility Visual Disturbances Auditory Sensitivity History 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

Effects of Abnormal Calcium Homeostasis Neurotransmitters Decreased Nicotinic Acetylcholine, Increased Glutamate, Decreased Dopamine Endocrine/Hormone Impaired Insulin, Oxytocin, Vasopressin, Melatonin, Cortisol, IGF1 Immune/Inflammatory Microglial activation, Th2 skewing, Proinflammatory cytokines Viral induced immune suppression Vascular/Smooth Muscle Gastrointestinal Increased Gastric Acid, Abnormal Motility, Increased Insulin release, Phopholipase C Membranes Decreased Cholesterol Mitochondria Stores excess Calcium which inhibits Oxidative Phosphorylation Poor Energy Production and Elevation of ROS (reactive oxygen species) Oxidative Stress Cross Talk between Calcium and ROS(peroxide, nitrous oxide, superoxide) Cause Damage to Endothelial Cells Motor – Sensory “Central Role of Voltage Gated Calcium Channels and Intracellular Calcium Homeostasis in ASD” N.B.S. Lozac Feb. 2007

Potential Biomarkers of Abnormal Calcium Homeostasis Decreased Antioxidant Status Elevated Pro-oxidants Elevated extracellular and intracellular Ca+2 Elevated ionized Calcium, elevated hair Ca+2 Elevated osteocalcin Elevated Alkaline Phosphatase (isoenzyme-bone) High CO2 Low Vitamin D Elevated urinary oxalates Hypoglycemia

Treating Excitotoxicity Avoid Excitotoxins/Dietary Modifications Use Glutamate Modulators Maximize Antioxidants Eliminate Toxins Treat and Identify Chronic Infections Alkalinize the Gut Limit excess Calcium, Ammonia, and Glutamate Support ATP production and the Mitochondria Provide adequate Methylation support Natural Anti-Inflammatories

Avoid Excitotoxins Substances 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 Infections Pesticides Heavy Metals Glutamate/MSG Sulfites/Hydrogen Sulfide Nitrites Propionates Benzoates

Excitotoxic Triggers Glutamate Excess Calcium Excess Ammonia Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols Excitotoxic Triggers Glutamate Monosodium Glutamate (MSG) Hydrolyzed Protein Modified Food Starch Natural Flavors Peas, Mushrooms, Tomatoes Parmesan Cheese Excess Protein Excess Calcium Excess Ammonia Excess Sulfur/Sulfite/ Hydrogen Sulfide Lead Aluminum Mercury EMF

Glutamate Modulators Magnesium Antioxidants Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols Glutamate Modulators Magnesium Antioxidants Leucine, Isoleucine, and Lysine Pycnogenol Rosemary, Lemon Balm Skull Cap, Chamomile Taurine GABA L- Theanine Vitamin K Gingko biloba Silymarin Flavinoids (curcumin, quercetin) Namenda (drug) Minocycline (antibiotic)

Anti-oxidants Excessive 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.  

Antioxidant Phytonutrients

Infections produce triggers that cause excitotoxicity! Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols Infections produce triggers that cause excitotoxicity! Viruses Bacteria- especially Strep and Clostridia……….. Yeast Parasites Lyme Mycoplasma Chronic 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.

Keys to treating chronic infections Identify type and location Aggressively clean up the gut Breakdown biofilm (diet, nutrition, and alkalinize) Treat infections with homeopathics and natural agents if possible Be patient Keep ammonia levels low Have a plan to manage die off

Ammonia If severely elevated rule out urea cycle disorder Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols If severely elevated rule out urea cycle disorder If mildly elevated consider possible causes Dysbiosis Recent infection Liver stress High protein diet or supplements BH4 (tetrahydrobiopterin deficiency) Symptoms Irritability, aggression, headache, head-banging, hyperactivity Treatment Strategies Avoid excess protein in diet Activated Charcoal, Fiber, Pectin, Zeolites Yucca / Aloe BH4 Butyrate Ammonia RNA (Yasko)

Vitamin K Protocol (Catherine Tamaro) Vit K Vit D Vit A DHA Bicarbonate Melatonin Avoid Calcium supplementation This Protocol is good for addressing excess extracellular calcium.

The Mitochondria is the powerhouse of each cell. Inside the Mitochondria, the Citric Acid Cycle produces ATP. ATP is the fuel for the cell. ATP provides energy.

ATP (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.

Mitochondrial 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 Acid Fumaric Acid Succinic Acid Alpha Keto Glutarate (careful)

Methylation & Beyond... Text

Methylation Support and Glutathione Production Combination of Pfeiffer Treatment Center, Defeat Autism Now, and Yasko Approach Understanding the underlying genetics is helpful in difficult cases CBS status, MTHFR, MTR, MTRR and COMT are helpful for understanding methylation issues Amino Acid testing and Cysteine, Glutathione, and Sulfate levels define picture. Undermethylation, COMT (- -), High Histamine Overmethylation, COMT (++), Low Histamine

COMT - - Treatment approach DAN Methyl B12 TMG DMG P5P Folinic Acid Creatine L Carnitine Glutathione(GSH) Yasko Intrinsic B12 Nucleotides Methylfolate BH4 GSH(limited) Emphasis on Methyl Donors: Methyl B12 SAMe Quercetin Gingko Curcumin Green Tea Phosphatidyl Serine Pfeiffer Methionine/SAMe Methyl B12 Calcium Magnesium P5P/B6 Zinc Vitamin C Phosphatidyl Serine Avoid Methyl Consumers: Folates DMAE Cyano B12 Niacinamide

COMT + + Treatment approach DAN Methyl B12 TMG DMG P5P Folinic Acid Creatine L Carnitine Glutathione Yasko Intrinsic B12 Nucleotides Methylfolate Hydroxy B12 Cyano B12 BH4 Limit Methyl Donors: Methyl B12 Quercetin Gingko Curcumin Green Tea Phosphatidyl Serine Pfeiffer Folic Acid Cyano B12 Niacinamide P5P, Vit B6 Zinc, Mb, Mn Vitamin C DMAE/Phosphatidyl Choline Avoid Methyl Donors: Methyl B12 Methyl Folate Methionine SAMe

Natural 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 LOX Quercetin 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.

Keys to Excess Glutamate Removal Avoid dietary Excitotoxins will help to minimize synaptic glutamate/aspartate. Keep neuronal ATP energy maximal by support of the Mitochondria Avoidance of hypoglycemia ATP 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. 

GABA/Glutamate Cycle Glutamine ADP NH3/ Ammonia ATP Amino acids p5p Mg ADP ATP Glutamine Glutamic Acid NH3/ Ammonia GABA Amino acids p5p Proline Decarboxylase (brain, kidney) NAD NADP NADH NADPH AKG Krebs/Mitochondria Glutamic acid dehydrogenase p5p Succinic Acid Krebs/Mitochondria

Additional Sources of Information Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols Additional Sources of Information Healing the New Childhood Epidemics (Autism, ADHD, Asthma and Allergies, Ken Bock MD Autism: Effective Biomedical Treatments, Pangborn and Baker Changing the Course of Autism, Jepson and Johnson Excitotoxins, the Taste that Kills, Russell Blaylock MD Envisioning a Brighter Future, Patty Lemur Websites www.autism.com www.safeminds.org www.autismone.org www.generationrescue.org www.vaccineawareness.org www.ddr.org

Thank You and Never Give Up Hope. Fine Tuning Detoxification Strategies and Individualizing Chelation Protocols Thank You and Never Give Up Hope.