Transcript Excitotoxicity in ASD

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
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Methylation Defects
Sulfation Defects
Cysteine Deficiency
Glutathione Deficiency (GSH)
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Dysbiosis (Yeast, Bad Bacteria, Parasites, Virus…)
Malabsorption
Maldigestion (enzyme deficiency, IgG food sensitivities, urinary peptides)
Autistic Enterocolitis/ Lymphonodular Hyperplasia
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Proinflammatory Cytokines
Microglial Activation
Th1/ Th2 skewing
Decreased Natural Killer Cell Activity
Increased Autoimmune Markers
• Gastrointestinal Dysfunction
• Immune System Dysregulation/Inflammation
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)
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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.
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
Immune
Activation
Infection/Toxin
Inflammation
Glutamate
Ammonia
Acidosis
Calcium
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.
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
• Calcium is one of the most important 2nd messengers
• Tightly regulated by stores, pumps and buffers
• VGCC- Voltage Gated Calcium Channels
– L type (LTCC)
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CNS
Immune system
GI tract
Inner Ear
• Symptoms of abnormal Calcium homeostasis
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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
1. Avoid Excitotoxins/Dietary Modifications
2. Use Glutamate Modulators
3. Maximize Antioxidants
4. Eliminate Toxins
5. Treat and Identify Chronic Infections
6. Alkalinize the Gut
7. Limit excess Calcium, Ammonia, and Glutamate
8. Support ATP production and the Mitochondria
9. Provide adequate Methylation support
10.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.
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Chronic Infections
Pesticides
Heavy Metals
Glutamate/MSG
Sulfites/Hydrogen Sulfide
Nitrites
Propionates
Benzoates
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
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Sulfur/Sulfite/
Hydrogen Sulfide
Lead
Aluminum
Mercury
EMF
Glutamate Modulators
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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
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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!
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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
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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
• If mildly elevated consider possible causes
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Dysbiosis
Recent infection
Liver stress
High protein diet or supplements
BH4 (tetrahydrobiopterin deficiency)
• Symptoms
– Irritability, aggression, headache, head-banging, hyperactivity
• Treatment Strategies
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Avoid excess protein in diet
Activated Charcoal, Fiber, Pectin, Zeolites
Yucca / Aloe
BH4
Butyrate
Ammonia RNA (Yasko)
Vitamin K Protocol
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(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
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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),
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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
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Malic Acid
Fumaric Acid
Succinic Acid
Alpha Keto Glutarate (careful)
Amy Yasko Diagram (2005)
Methylation & Beyond...
Text
Methylation Support and Glutathione Production
• Combination of Pfeiffer Treatment Center, Defeat
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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
Yasko
Pfeiffer
Methyl B12
TMG
DMG
P5P
Folinic Acid
Creatine
L Carnitine
Glutathione(GSH)
Intrinsic B12
Nucleotides
Methylfolate
BH4
GSH(limited)
Emphasis on
Methyl Donors:
Methionine/SAMe
Methyl B12
Calcium
Magnesium
P5P/B6
Zinc
Vitamin C
Phosphatidyl Serine
Methyl B12
SAMe
Quercetin
Gingko
Curcumin
Green Tea
Phosphatidyl Serine
Avoid Methyl Consumers:
Folates
DMAE
Cyano B12
Niacinamide
COMT + + Treatment approach
DAN
Yasko
Pfeiffer
Methyl B12
TMG
DMG
P5P
Folinic Acid
Creatine
L Carnitine
Glutathione
Intrinsic B12
Nucleotides
Methylfolate
Hydroxy B12
Cyano B12
BH4
Folic Acid
Cyano B12
Niacinamide
P5P, Vit B6
Zinc, Mb, Mn
Vitamin C
DMAE/Phosphatidyl
Choline
Avoid Methyl Donors:
Limit Methyl Donors:
Methyl B12
Quercetin
Gingko
Curcumin
Green Tea
Phosphatidyl Serine
Methyl B12
Methyl Folate
Methionine
SAMe
Natural Anti-inflammatory Agents
• The excitotoxic process does much of its damage through initiating
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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 alphaketoglutarate, 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
Mg
Amino acids
NH3/ Ammonia
ATP
Glutamic Acid
Proline
NAD
NADP
Decarboxylase
(brain, kidney)
p5p
GABA
p5p
Succinic Acid
Krebs/Mitochondria
Glutamic acid dehydrogenase
NADH
NADPH
AKG
Krebs/Mitochondria
Additional Sources of Information
• Healing the New Childhood Epidemics (Autism, ADHD,
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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.