Transcript PowerPoint - Dr. Theoharides

Novel Treatment Approaches to Autism: How genes
and environment contribute to brain inflammation
and symptoms
Theoharides C. Theoharides,
MS, PhD, MD, FAAAAI
Professor 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
[email protected]
www.mastcellmaster.com
Clinical Pharmacologist, Massachusetts Drug
Formulary Commission (1986-2012)
Most Common Problems in Children with ASD
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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
Allergic-Like Symptoms
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Allergies
Angioneurotic edema
Atopy
Atopic dermatitis
Eczema
Food allergy
Food intolerance
Idiopathic urticaria
Idiopathic mast activation disorder
Mastocytosis
Mast cell activation syndrome
Edvard Munch, The Scream (Skrik, 1893)
Non-IgE food allergy
Urticaria pigmentosa
Copyright Dr. T.C. Theoharides
Mast Cells Are Tissue Immune Cells Involved in All
the Pathological Processes Suspected in Autism
Mediators
Triggers
Allergen/IgE
C3a, C5a
IL-1, IL-33
Endothelin Normal mast cells
LPS
Neuropeptides
Thrombin
Activated mast cell
Histamine
Chymase
Tryptase
Leukotrienes
PAF
Prostaglandins
Chemokines
IL-1, IL-6, IL-8
GM-CSF, TNF-
VEGF
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
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The Mast Cell Is the “Canary” of the Body
Mast cell activation by environmental triggers
Bacterial 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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p=0.027
p=0.005
Serum NT level (pg/ml)
250
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Control A
(n=8)
Control B
(n=16)
ASD
(n=24)
Funded by Safe Minds and the Autism Collaborative
Angelidou A et al. J Neuroinflammation. 2010 Aug 23;7:48.
Copyright Dr. T.C. Theoharides
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.
Role of Epigenetics
How environmental and stress factors
influence gene activation
72, October 20, 2011
Many gene mutations discovered, but only explain about 5% of ASD cases.
Twin pair study indicates that >60% of influence is not genetic.
Mast cell & Microglia
triggers
Calcium influx
via receptor
PI3K
cell activation
PTEN
ASD
TSC1 TSC2
ASD
cell number
AKT
ASD
cell number
ASD
Rapamycin
mTORC1
Luteolin
S6K
4E-BP1
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
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Beneficial Effect of Flavonoids in Brain Inflammation
Middleton E Jr, Kandaswami C, Theoharides TC.
Pharmacol Rev. 2000 52(4):673-751. Review.
Flavonoids are potent:
1. Anti-oxidant and
2. Anti-inflammatory
Inhibitory Effect of Luteolin on ProInflammatory
Mediator Release from Human Mast
Inhibition of inflammatory molecules by quercetin
Cells
from
human mast cells
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90
4. Metal chelators
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IL-6
IL-8
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80
Percent inhibition
3. Mast cell inhibitors
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Histamine
Tryptase
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TNF-alpha
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Dec. 20, 2009
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Theoharides et al. Expert Opin. Pharmacotherapy (2009) 10 (13):2127-2143
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Cochrane Database Syst Rev.
2010 Aug 4;(8):CD004677
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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.
Allergic, environmental, immune, infectious,
Stress and toxic triggers
(Foods, IL-1, LPS, CRH, mercury, PCBs)
Mast
cell
Blood
vessel
Quercetin
Luteolin
Rutin
Disruption of the
blood-brain barrier
Mast cell-derived
inflammatory, neurotoxic
and oxidative stress
mediators
(IL-6, TNF, tryptase)
Disruption of the
gut-blood barrier
GOAL
Luteolin formulation to increase
absorption and brain levels
Brain
Inflammation
Stimulation
Inhibition
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
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
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29 boys and 8 girls)
Some ASD children
cannot metabolize
Polyphenolic
Compounds leading to:
• Hyperactivity
• Irritability
• Aggressiveness
• Inability to sleep
• Inappropriate laughter
• Self-injurious behavior
Phenolic groups of quercetin,
luteolin and Pycnogenol
Test-Administer teaspoon
of acetaminophen
(Tylenol)
Reduce-Administer
NoFenol (Houston
Enzymes)
Pycnogenol has 15, quercetin has 5
and luteolin 4 phenolic groups
TNF (pg/mL /106 cells)
Comparison of Luteolin and Methoxyluteolin on
Inhibition of Human Mast Cell TNF Release
SP (2 μM): Lut (μM): Me-Lut (μM): -
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Sofia’s Progress
Dx: Autistic disorder
11/2010-Non verbal
Started on NeuroProtek:
6/2011-”Sentences, singing and
drawing”
Christina’s Progress
Dx: Autistic disorder
3/2011-Nonverbal
Started on NeuroProtek:
4/2011-”Can I play with you?”
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Mack’s Progress
Dx: Autistic disorder
11/2010-Non verbal
Started on NeuroProtek:
12/2011-”Xmas carrols, drawing
first Xmas card ever,”
6/2011-”Sentences, singing
1/2012-”Full conversation,
attending regular middle school.”
Research Funding:
DK62861 NIDDK
AR47652 NIAMS
NS071361 NINDS
NS55681 NINDS
AR60951 NIAMS
NS66205 NIH
Autism Research
Collaborative
Safe Minds
Autism Research
Institute
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http://www.mastcellmaster.com
http://www.neuroprotek.com
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http://www.youtube.com/watch?v=yGyb0fK9ohk&feature=relmfu
http://www.youtube.com/watch?v=pNQsK9PQL3c
http://www.youtube.com/watch?v=3QFa36TBtvA
Disclosure
Dr. 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