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Novel Treatment Approaches to Autism: How genes and environment contribute to brain inflammation
and symptomsTheoharides C. Theoharides,
MS, PhD, MD, FAAAAIProfessor of Pharmacology, Internal Medicine and Biochemistry; Associate Professor of Psychiatry
Director, Molecular Immunopharmacology and Drug Discovery Laboratory
Tufts University School of Medicine-Tufts Medical Center Boston, MA, USA
Clinical Pharmacologist, Massachusetts Drug Formulary Commission (1986-2012)
Most Common Problems in Children with ASD
• Brain inflammation (high IL-6 and TNF)• Blood-brain-barrier disruption• Brain fog• Food allergies/intolerance/GI complaints• Inability to socialize• Lack of eye contact and attention• Loss of speech• Mitochondrial dysfunction• Reduced sociability• Skin eruptions
Copyright Dr. T.C. Theoharides
Allergic-Like Symptoms• Allergies• Angioneurotic edema• Atopy • Atopic dermatitis• Eczema• Food allergy • Food intolerance • Idiopathic urticaria• Idiopathic mast activation disorder• Mastocytosis • Mast cell activation syndrome • Non-IgE food allergy• Urticaria pigmentosa
Edvard Munch, The Scream (Skrik, 1893)
Mast Cells Are Tissue Immune Cells Involved in All the Pathological Processes Suspected in
Autism
Allergen/IgE
C3a, C5a
IL-1, IL-33
Endothelin
LPS
Neuropeptides
Thrombin
Histamine
Chymase
Tryptase
Leukotrienes
PAF
Prostaglandins
Chemokines
IL-1, IL-6, IL-8
GM-CSF, TNF-VEGF
Triggers Mediators
Activated mast cell
Normal mast cells
Mast cells can be activated by many environmental, infectious and stress triggers leading to the release of mediators with potent vasodilatory, nociceptive, and inflammatory properties
Copyright Dr. T.C. Theoharides
Copyright Dr. T.C. Theoharides 10Copyright Dr. T.C. Theoharides
The Mast Cell Is the “Canary” of the Body
Mast cell activation by environmental triggersBacterial and viral antigens, environmental toxins such as
polychlorinated biphenyl (PCB) and mercury, preservatives, toxins.
Mercury chloride induces significant VEGF release and augments SP-induced VEGF release
Neurotensin Is a Mast Cell Trigger Present Both in the Brain and the Gut
• NT is a peptide originally isolated from the brain.
• Most NT receptors in the brain are in the Broca area responsible for language, often lost in ASD children.
• NT is neurotoxic and can induce seizures.
• NT is present also in the GI tract, where it can induce intestinal inflammation.
• NT can activate immune cells, and act together with corticotropin-releasing hormone (CRH), secreted under stress, to stimulate mast cells
Donelan et al. PNAS USA 103:7759-7764, 2006.
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Copyright Dr. T.C. Theoharides
0
50
100
150
200
250
p=0.027
p=0.005
Control A Control B ASD (n=8) (n=16) (n=24)
Seru
m N
T le
vel (
pg/m
l)
Funded by Safe Minds and the Autism CollaborativeAngelidou A et al. J Neuroinflammation. 2010 Aug 23;7:48.
Serum mitochondrial DNA and anti-mitochondrial antibodies are present in young children with autism
Funded by the Autism Research Collaborative and Theta Biomedical, Inc.Zhang et al. J Neuroinflammation. 2010, In press.Funded by the Autism Research Collaborative and Theta Biomedical, Inc.Zhang et al. J Neuroinflammation. 2010, In press.
Role of Epigenetics
How environmental and stress factors influence gene activation
Many gene mutations discovered, but only explain about 5% of ASD cases.Twin pair study indicates that >60% of influence is not genetic.
72, October 20, 2011
Mast cell & Microglia triggers
PI3K
AKT
mTORC1
PTEN
TSC1 TSC2
S6K 4E-BP1
cell number ASD
cell activation
cell number
ASDRapamycin
Luteolin
ASD
ASD
Calcium influx via receptor
Cell size & proliferation
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Structures of quercetin and luteolin
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• Flavonoids are lipophilic (do not dissolve in water)
• Less than 5% are absorbed orally
• Are heavily metabolized (broken down in the liver)
• Need to formulate with oil in liposomes
• Need to use in proper combination to permit some action in GI and some in brain
• www.algonot.com
47
Beneficial Effect of Flavonoids in Brain Inflammation
Flavonoids are potent:
1. Anti-oxidant and
2. Anti-inflammatory
3. Mast cell inhibitors
4. Metal chelators
Middleton E Jr, Kandaswami C, Theoharides TC. Pharmacol Rev. 2000 52(4):673-751. Review.
Copyright Dr. T.C. Theoharides
0
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50
60
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100
Histamine Tryptase IL-6 IL-8 TNF-alpha
Perc
en
t in
hib
itio
n
*
** *
*
Inhibition of inflammatory molecules by quercetin from human mast cells
Inhibitory Effect of Luteolin on Pro-Inflammatory
Mediator Release from Human Mast Cells
Dec. 20, 2009 Copyright Dr. T.C. Theoharides 48
Theoharides et al. Expert Opin. Pharmacotherapy (2009) 10 (13):2127-2143
Copyright Dr. T.C. Theoharides
Cochrane Database Syst Rev.
2010 Aug 4;(8):CD004677.
In a recent study of spontaneous reporting of adverse drug - drug interaction in Italy, the incidence was 9.8% for two drugs but increased to 88.3% for 8 drugs or more there is less information on drug-supplement interaction. However, it was reported that 33.4% of patients using antipsychotics also took traditional Chinese medicine concurrently; 7.2% of these patients had worse outcomes as compared to 4.4% of those using antipsychotic alone.
Blood vessel
Mast cell
Mast cell-derived inflammatory, neurotoxic
and oxidative stress mediators
(IL-6, TNF, tryptase)
Disruption of the gut-blood barrier
Brain Inflammation
Disruption of the blood-brain barrier
Inhibition
Stimulation
Allergic, environmental, immune, infectious, Stress and toxic triggers
(Foods, IL-1, LPS, CRH, mercury, PCBs)
Quercetin
LuteolinRutin
GOALLuteolin formulation to increase
absorption and brain levels
Flavonoids are poorly absorbed
• Flavonoids are lipophilic (do not dissolve in water)
• Less than 5% are absorbed orally
• Are heavily metabolized (broken down in the liver)
• Need to formulate with olive kernel oil
• Need to use in proper combination to permit actions in both GI and in brain
Relevant TCT Patents and Trademark:
US patents No. 6,624,148; 6,689,748; 6,984,667, and EPO 1365777, which cover methods and compositions of mast cell blockers, including flavonoids, US patents 7,906,153 and 12/861,152 (allowed) for treatment of neuro-inflammatory conditions, as well as US patent applications No.12/534,571 and No.13/009,282 for the diagnosis and treatment of autism.
Trademark NeuroProtek® US 3,225,924
Benefits of NeuroProtek®
Properties Benefits
Luteolin
Anti-oxidant Reduces brain oxidative stress
Anti-inflammatory Reduces brain inflammation
Microglia inhibitor Reduces brain inflammation
Anti-cytokine Inhibits IL-6 production
Stabilizes blood vessels Protects against BBB disruption
Is neuroprotective Protects neuronal damage
Reverses autistic-like behavior in mice Has beneficial effect in vitro
Olive Kernel Oil
Anti-inflammatory Reduces gut and brain inflammation
Contains hydroxytyrosol and oleocanthal Inhibit beta-amyloid plaque formation
Reverses Alzheimer’s condition in mice Has beneficial effect in vitro
* (n= 37, 4-14 years old; 29 boys and 8 girls)
* (n= 37, 4-14 years old; 29 boys and 8 girls)
Benefits of Neuroprotek in autism*
Symptoms Approximate improvement of children
Stool color, shape, smell 28/37
“Allergic problems” 19/37
Eye contact 15/37
Retention of learned aspects 15/37
Social interaction 14/37
Attention to directions 12/37
Speaking words/sentences 4/37
Hyperactivity/Aggression -
Phenolic groups of quercetin, luteolin and Pycnogenol
Pycnogenol has 15, quercetin has 5 and luteolin 4 phenolic groups
Some ASD children
cannot metabolize
Polyphenolic
Compounds leading to:• Hyperactivity• Irritability• Aggressiveness• Inability to sleep• Inappropriate laughter• Self-injurious behavior
Test-Administer teaspoon of acetaminophen (Tylenol)
Reduce-Administer NoFenol (Houston Enzymes)
Comparison of Luteolin and Methoxyluteolin on Inhibition of Human Mast Cell TNF Release
SP (2 μM): - + + + + + + +Lut (μM): - - 10 50 100 - - -
Me-Lut (μM): - - - - - 10 50 100
TN
F (
pg
/mL
/106
cell
s)
SP (2 μM): - + + + + + + +Lut (μM): - - 10 50 100 - - -
Me-Lut (μM): - - - - - 10 50 100
TN
F (
pg
/mL
/106
cell
s)
Sofia’s Progress
Dx: Autistic disorder
11/2010-Non verbal
Started on NeuroProtek:
6/2011-”Sentences, singing and drawing”
Christina’s Progress
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Dx: Autistic disorder
3/2011-Nonverbal
Started on NeuroProtek:
4/2011-”Can I play with you?”
Mack’s Progress
Dx: Autistic disorder11/2010-Non verbalStarted on NeuroProtek:12/2011-”Xmas carrols, drawing first Xmas card ever,” 6/2011-”Sentences, singing1/2012-”Full conversation, attending regular middle school.”
Research Funding:
DK62861 NIDDK AR47652 NIAMS NS071361 NINDS NS55681 NINDS
AR60951 NIAMS NS66205 NIH
Autism Research CollaborativeSafe MindsAutism Research Institute
Research Funding:
DK62861 NIDDK AR47652 NIAMS NS071361 NINDS NS55681 NINDS
AR60951 NIAMS NS66205 NIH
Autism Research CollaborativeSafe MindsAutism Research Institute
• http://www.mastcellmaster.com
• http://www.neuroprotek.com
• http://www.youtube.com/watch?v=yGyb0fK9ohk&feature=relmfu• http://www.youtube.com/watch?v=pNQsK9PQL3c• http://www.youtube.com/watch?v=3QFa36TBtvA
DisclosureDr. Theoharides is Medical Director
and holds a major interest in Algonot, LLC
www.algonot.com
Portion of any profits will be donated to autism research
