neuroinflammation in autism and its resemblance to...
TRANSCRIPT
Neuroinflammation in autism and its resemblance to adult neurodegenerative diseaseDEBBY HAMILTON, M.D., MPH
1
Objectives
Understand the underlying neuropathology of
autism
Understand that autism has both systemic and
neuroinflammation
Discuss the similarity of neuropathology between
autism and adult neurodegenerative diseases
and the implication of this information.
Learn about treatment options for
neuroinflammation and oxidative stress
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DSM-5 Diagnosis: ASD 3
Prevalence of ASD
About 1 in 68 children in 2012:CDC’s Autism and Developmental Disabilities Monitoring (ADDM) Network. From 1 in 150 children in 2000
ASD is about 4.5 times more common among boys (1 in 42) than among girls (1 in 189).
Studies in Asia, Europe, and North America have identified individuals with ASD with an average prevalence of between 1% and 2%.
About 1 in 6 children in the United States had a developmental disability in 2006-2008, ranging from mild disabilities such as speech and language impairments to serious developmental disabilities, such as intellectual disabilities, cerebral palsy, and autism.
https://www.cdc.gov/ncbddd/autism/data.html
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Neurodegenerative diseases
➢ 5 million Americans suffer from Alzheimer's disease
➢ 1 million from Parkinson's
➢ 400,000 from multiple sclerosis (MS)
➢ 30,000 from amyotrophic lateral sclerosis (ALS or
Lou Gehrig's disease)
➢ 30,000 from Huntington's
➢ If left unchecked 30 years from now, more than 12
million Americans will suffer from
neurodegenerative diseases.
http://neurodiscovery.harvard.edu/challenge
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Comparison of symptoms
Autism
Communication
problems
Social impairment
Motor processing issues
Cognitive impairments
Repetitive speech and
activities
Memory problems
Mood and behavioral
issues
Alzheimer’s
Communication
problems
Social impairment
Motor processing issues
Cognitive impairments
Repetitive speech and
activities
Memory problems
Mood and behavioral
issues
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Common Medical issues in ASD
Gastrointestinal issues
Seizures
Immune Dysfunction
Allergies
Autoimmune issues
Frequent infections
Sleep disorder
Feeding disorder
Nutritional Deficiency
ADHD
Mood disorders
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Immune Deficiencies/Imbalance
in Autism
Increased allergies to food/environment
Decreased NK cell number and function
Low number of helper T-cells (CD4+ cells)
Depressed T-cell responses to activation
Low sIgA (poor mucosal immunity-GI issues)
Autoantibodies: myelin basic protein, neuronal
filament
Maternal increase in Th17 cells with increase in IL-
17A
Wong H. et al. Maternal IL-17A in autism. Autism. 2017 Apr 25.
Cohly HH. Immunological findings in autism. In. Rev Neurobiol. 2005;71:317-41.
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Comparison of pathology
Autism Spectrum
Disorders
Mitochondrial
Dysfunction
Oxidative Stress
Disrupted Gut-Brain-
Microbiome
Connection
Systemic Inflammation
Neuroinflammation
Neurodegenerative
disease
Mitochondrial
Dysfunction
Oxidative Stress
Disrupted Gut-Brain-
Microbiome
Connection
Systemic Inflammation
Neuroinflammation
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Oxidative Stress in Autism
Research comparing anti-oxidant markers and
markers of lipid peroxidation to assess oxidative
stress
Study population: 20 children with ASD
25 matched healthy controls
Results: Positive in ASD children younger than 6
yrs
Decreased anti-oxidant markers with SOD and
GSH-PX
Increase in lipid peroxidation marker MDA
Meguid, N.A., Dardir, A.A., Abdel-Raouf, E.R. et al. Biol Trace Elem Res (2011) 143: 58.
doi:10.1007/s12011-010-8840-9
10
“”
Oxidative stress has been implicated in the
progression of Alzheimer's disease (AD), Parkinson's
disease (PD) and other neurodegenerative diseases.
Oxidative stress leading to free radical attack on
neural cells contributes calamitous role to
neurodegeneration. Toxicity of ROS contributes to
protein misfolding, glia cell activation, mitochondrial
dysfunction and subsequent cellular apoptosis.
OXIDATIVE STRESS IN
NEURODEGENERATIVE DISEASE
Chen X, Guo C, Kong J. Oxidative stress in neurodegenerative
diseases. Neural Regeneration Research. 2012;7(5):376-385.
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Connection between
Systemic inflammation and
Neuroinflammation in ASD
Comparison of serum markers of inflammation: IL-1B, Il-
6, IL-10, and endotoxins
22 adult patients with severe autism
28 control patients
Results:
Higher endotoxin levels in adults with autism P<0.001
Higher IL-1B and IL-6 p<0.05
Higher endotoxin levels associated with worse
socialization markers in adults with autism
Emanuele E. et al. Low-grade endotoxemia in patients with severe autism. Neuroscience Letters 471. 2010:
162-165
12
Systemic Inflammation in
Neurodegenerative diseases
Study: 300 patients with Alzheimer’s
Cognitive assessment, serum inflammatory
markers and document with caregiver all
systemic inflammatory events
Results:
Acute systemic inflammatory events correlated
with 2 times cognitive decline
Increase in TNF-alpha in serum
High baseline TNF-alpha: 4 time rate of increase
rate of cognitive decline
Holmes C et al. Systemic inflammation and disease progression in
Alzheimer’s disease. Neurolog.2009. Vol 7(10):768-774.
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Microglia and neurodegeneration:
The role of systemic inflammation
GliaVolume 61, Issue 1, pages 71-90, 6 JUN 2012 DOI: 10.1002/glia.22350http://onlinelibrary.wiley.com/doi/10.1002/glia.22350/full#fig4
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Neuroinflammation:
The Brain on Fire15
Neuroglia:Neuron Support Cells
Oligodendrocytes:
produce myelin
Microglia: immune
macrophages in the
nervous system
Astrocytes: Regulators of
neuronal growth and
survival
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Microglia: Functions
Phagocytosis
Synaptic Pruning
Development of CNS
Maintenance of CNS cells
Instigate inflammation
Repair and regeneration in
CNS inflammation
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Activated Microglia:
Cycle of inflammation and repair
1. Rapid proliferation of microglial cells
2. Migrate to site of insult or infection
3. M1 activated microglia: neurotoxic with release
of pro-inflammatory cytokines including TNF-
alpha, IL-1B, IL-6, COX, Reactive oxygen species
(ROS), Nitric oxide
4. Engulf dying cells, infectious agents, toxic
proteins, and cell debris
5. M2 activated microglia: secrete anti-
inflammatory cytokines for repair including: IL-
10, TGF-B, enzymes to inhibit ROS production
(arginase), proteins to maintain extra-cellular
matrix
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Astrocytes: Functions
Induce formation of neuronal synapses
Formation and maintenance of BBB
Neurotransmission: component of tripartite synapse model
Homeostasis and turnover of glutamate
Metabolic regulation
Ion balance maintenance
Key role in development of the nervous system
19
Vargas DL. Et al. Neuroglial activation and
neuroinflammation in the brain of patients with
autism. Annals of Neurology. 2005. 57,67-81.
A: normal cerebellum in
control patient
B-C: atrophic
cerebellum in a patient
with autism with loss of
purkinje and granular
cells
D-K: activated microglial
and inflammatory cells
20
Young AMH, Campbell E, Lynch S, Suckling J, Powis SJ. Aberrant NF-KappaB Expression in Autism Spectrum Condition: A Mechanism for Neuroinflammation. Frontiers in Psychiatry. 2011;2:27.
21
A: Western Blot Image of
anti-NF-kB p65 Ab’s
B: Relative expression of
NF-KB p65 subunit
C: Image of
fractionaded samples
probed with anti-NF-KB
p65
Summary of Neuroinflammation markers in ASD
Microglial activation
Astrocytic activation with elevated levels of
GFAP(glial fibrillary acidic protein)
Proinflammatory profile of cytokines in the brain,
CSF and blood
Nuclear factor kappa-light-chain-enhancer of
activated B cells (NF-κB) activation
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Alzheimer’s
Neuroinflammation
Accumulation of protein aggregates
Extracellular: B-amyloid plaques
Intracellular: Neurofibrillary tangles (NFT)
Cause loss of synaptic function leading to
neuronal death
Microglial activation
Astrocyte activation
Pro-inflammatory cytokines near B-amyloid
protein deposits and NFT
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Brain inflammation accompanies
amyloid in early cognitive
impairment
Study: 42 patients with mild cognitive
impairment, 22 controls
Results from PET scans
62% (26 out of 42) patients with mild cognitive
impairment: increased cortical amyloid
deposition
85% (22 out of 26) patients with increased amyloid
had clusters of activated microglial cells by the
amyloid
Parbo P et al. Brain inflammation accompanies amyloid in the majority
of mild cognitive impairment cases due to Alzheimer’s disease. Brain.
2017. 140(7):2002-2011.
25
Parkinson’s
Neuroinflammation
Loss of dopamine neurons in the
substantia nigra
Alpha-synuclein (Lewy body) protein
inclusions in the nervous system
Microglial activation
Increase in pro-inflammatory cytokines
Subramaniam SR et al. Targeting microglial activation states as a
therapeutic avenue in Parkinson’s disease. Frontiers Aging Neurosci.
2017. June
26
Are children with Autism at an increased risk of Alzheimer’s
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Implications for future of children
with autism spectrum disorders
One research study: Transcranial magnetic stimulation to check for
hyperplasticity in Asperger’s adults with normal cognitive capability: measured movement of the hand
Decrease plasticity associated with Alzheimer’s
Found increased plasticity in Asperger’s adults so hypothesis that people with autism would be protected
L.M. Oberman and A. Pascual-Leone. Hyperplasticity in autism spectrum disorder confers protection from Alzheimer’s disease. Medical Hypotheses. Published online June 17, 2014.
28
“”
Down's syndrome (DS), which is
characterized by premature aging, that
there is enhanced oxidative stress resulting
from the aberrant expression of CuZn
superoxide dismutase (CuZn SOD).
…….. DS cells are impaired in their ability to
repair oxidative damage to mtDNA
compared to age-matched control cells.
DOWN’S SYNDROME: INCREASED AGING
AND EARLY ALZHEIMER’S DISEASE
Defective repair of oxidative damage in mitochondrial DNA in Down's syndrome. Druzhyna N. Et al. Mutation Research
29
Implications for future of
children with autism
spectrum disorders?
30
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Treatment
Oxidative Stress
Systemic Inflammation
Neuroinflammation
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Diagnosis:
Oxidative Stress
Test for DNA/RNA damage: 8-hydroxydeoxyguanosine (8-OHdG)
Urine and blood
Test for lipid peroxidation: 8-isoprostane
Urine and blood
Anti-oxidant Reserves and enzyme function: Total antioxidant capacity, glutathione peroxidase, superoxide dismutase (SOD) Blood tests
Glutathione blood level (Need to draw and put on ice immediately to be accurate)
33
Support
for
oxidative
stress
Anti-oxidants to combat oxidative stress
Glutathione
Molecular Hydrogen (H2 : Hydrogen gas)
Vitamin E: mixed tocopherols and tocotrienols
Curcumin
Tea: EGCG
Resveratrol
N-acetyl-cysteine
34
Nrf2: Nuclear Factor 2
Master regulator of the antioxidant
system
Mechanism: A Nrf2 activator
releases protein into the cell
nucleus where it binds to DNA and
activates anti-oxidant enzymes
such as catalase, glutathione
peroxidase, and superoxide
dismutase and these enzymes can
neutralize up to 1 million free
radicals
Researched Nutritionals
35
Natural Nrf2 Activators
Curcumin
Resveratrol
Sulforaphane
Flavanols: tea (EGCG),
chocolate
Vitamin D
Coffee
Molecular hydrogen
36
Molecular Hydrogen: H2
Summary
1.) Anti-oxidant for dangerous hydroxyl radical without destroying free radicals needed for metabolism
2.) Activates Nrf2 anti-oxidant cascade including glutathione peroxidase, catalase, and superoxide dismutase (SOD)
3.) Decreases pro-inflammatory cytokines through cell signaling
4.) Promotes mitochondrial ATP energy function
5.) Crosses the Blood Brain Barrier
1Molecular hydrogen as a preventive and therapeutic medical gas: initiation, development and potential of hydrogen medicine, Ohta S., Pharmacology & Therapeutics, Volume 144, Issue 1, October 2014, Pages 1–11
2Clinical Effects of Hydrogen Administration: From Animal and Human Diseases to Exercise Medicine, Nicolson G. et al., International Journal of Clinical Medicine, 2016, 7, 32-76
37
Neuroinflammation: Molecular
Hydrogen
Research: animal study with hydrogen rich
saline
3 groups: control, induced amyloid-beta neural
inflammation, and induced amyloid inflammation
plus hydrogen saline
Results:
Hydrogen-saline prevented amyloid-beta
induced neuroinflammation and oxidative stress
Wang C et al. Hydrogen-rich saline reduces oxidative stress and inflammation by inhibition of JNK and NF-KB activation in a rat model of amyloid-beta induced Alzheimer’s disease. Neuroscience Letters. 2011. 491(2):127-132.
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Cognitive Impairment:
Improvement with Molecular
hydrogen
Placebo controlled study in senescence accelerated animals
30 days of molecular hydrogen water:
Prevented age-related declines in cognitive ability seen in controls
Increased brain serotonin levels and
Elevated serum antioxidant activity.
Drinking hydrogen water for 18 weeks inhibited neurodegeneration in hippocampus, while marked loss of neurons was noted in control
Gu, Yeunhwa et al. “Drinking Hydrogen Water Ameliorated Cognitive Impairment in Senescence-Accelerated Mice.” Journal of clinical biochemistry and nutrition (2010).
39
Molecular Hydrogen:
Parkinson’s Disease
Randomized placebo controlled trial
48 weeks consuming either 1000 ml of molecular
hydrogen water or placebo
Statistically significant improvement in the
molecular hydrogen group: Unified Parkinson’s
Disease Rating Scale (UDPRS)
Worsening disease rating in the placebo group
Yoritaka, A., et al., Pilot study of H(2) therapy in Parkinson’s disease: A randomized double-blind placebo-controlled trial. Movement Disorders, 2013.
40
H2 Absorb™for a healthier life
41
42
What are the functions of Glutathione?
1. Master Antioxidant
2. Reduces Free Radicals
3. Detoxifies Chemicals
4. Chelates Heavy Metals
5. Protects Mitochondrial DNA
6. Cellular Anti-inflammatory compound
7. Storage and transport of cysteine
8. Enhances immune function
and transport of cysteine
43
44
Neurodegeneration 45
Brain Glutathione Levels – A Novel Biomarker for Mild
Cognitive Impairment and Alzheimer’s Disease. Mandal,
Pravat K. et al. Biological Psychiatry , Volume 78 , Issue 10 , 702
- 710
Alzheimer’s disease dependent reduction of GSH
was observed in both Hippocampus and Frontal
C (p < 0.001).
GSH reduction in these regions correlated with
decline in cognitive functions.
Hippocampal GSH discriminates between mild
cognitive impairment and healthy controls
46
Sinha R. Et al. Oral supplementation with liposomal glutathione elevates body stores of glutathione and markers of immune function. European Journal of Clinical Nutrition advance online publication, 30 August 2017; doi:10.1038/ejcn.2017.132.
A clinical trial using Tri-
Fortify™ liposomal
glutathione showed
efficacy in raising
intracellular reduced
glutathione levels (GSH)
along with natural killer
cell function while also
decreasing oxidative
stress markers.
47
Tri-Fortify™clinical research summary
48
Tri-Fortify™ clinical research summary
49
Tri-Fortify™ clinical research summary
50
Tri-Fortify™
liposomal glutathione
Available in two natural flavors:
Watermelon
Orange
450 mg of glutathione per serving
50 mg of vitamin C
Proven Heat Stable
3rd party lab tested
1040F/400C / 75% humidity – 90 days
Result: exceed label claim
GMO-free (3rd party lab tested)
51
52
Natural
Anti-
Inflammat
ories
Molecular Hydrogen (H2 : Hydrogen gas)
Glutathione
Curcumin
Tea: EGCG
Resveratrol
N-acetyl-cysteine
Boswellia
White Willow Bark
Omega-3 fatty acids
53
Review of polyphenols:
Curcumin, Resveratrol,
Quercetin, Luteolin
Decrease sustained
activation of the
microglia (innate
immune cells of the CNS)
Role of dietary phenols in mitigating microglia mediated neuroinflammation
Neuromolecular Med 2016 Sep. By Rangarajan P et al
Research involving aluminum
induced neuroinflammation
Results:
Significant attenuation of
inflammatory markers
Decrease in amyloidogenic
mediators
Improvement in pathology seen in
brain cortexes
Zaky A. Et al. A combination of resveratrol and curcumin is effective against Aluminum Chloride induced neuroinflammation in rats. J. Alzheimer’s Dis. 2017 Feb 7.
Liu J-B, Zhou L, Wang Y-Z, et al. Neuroprotective Activity of (−)-Epigallocatechin Gallate against Lipopolysaccharide-Mediated Cytotoxicity. Journal of Immunology Research. 2016.
EGCG pretreatment of
macrophages significantly
inhibited LPS-mediated
induction of these cytokines.
EGCG-pretreated and LPS-
activated macrophage cultures
was found to be less cytotoxic
to neurons than that from non-
EGCG-pretreated and LPS-
activated macrophage
cultures.
56
CytoQuel®: healthy cytokine and
inflammation support
Black Tea Extract
Much stronger antioxidant than green tea
Highest EGCG Content - 50%
CurcuWin®
46X absorption of standard curcumin*
35X absorption of BCM-95®*
6X absorption of Meriva®*
Delta Gold® Tocotrienols
Pure delta & gamma
No tocopherols = better absorption
N-Acetyl-cysteine (NAC)
Resveratrol (Natural Trans-Resveratrol)
* Comparative Absorption of Curcumin Formulations. Jager R. Et al Nutr J 2014 Jan 24;13(1):11.
57
CytoQuel®: healthy cytokine
and inflammation support
Suggested Use
Take one capsule per day with a meal for the
first week, and three capsules per day with a
meal in week two and beyond, or use as
directed by your healthcare professional.
They may be taken at the same meal or spread
amongst your meals.
For best results take away from Vitamin E
(tocopherol).
Herx response suggested use: 2 bid
58
CytoQuel®for healthy cytokine and inflammation support
59
Summary: Support for oxidative
stress, inflammation, and
neuroinflammation
CytoQuel® - support healthy
cytokine activity and
manage oxidative stress and
inflammation
H2Absorb™ -manage oxidative stress
and inflammation,
mitochondrial function
Tri-Fortify™ -Liposomal glutathione
60
References for Anti-oxidants
Abraham J. et al. Consuming a diet supplemented with resveratrol reduced infection related
neuroinflammation and deficits in working memory in aged mice. Rejuvenation Research.
2009 Dec. Vol 12(6).
Bhandari R. et al. Resveratrol suppresses neuroinflammation in the experimental paradigm of
autism spectrum disorders. Neurochem Int. 2017 Feb; 103:8-23.
Dominiak K. et al. Critical need for clinical trials: an example of a pilot human intervention
trial of a mixture of natural agents protecting lymphocytes against TNF-alpha induced
activation of NF-kB. Pharm Res. 2010 June;27(6)
Dukhande VV. et al. Neuroprotection against neuroblastoma cell death induced by depletion of mitochondrial glutathione. Apoptosis : an international journal on programmed
cell death. 2013;18(6):702-712.
Hoppe JB. et al. Curcumin protects organotypic hippocampal slice cultures from Abt-a42-
induced synaptic toxicity. Toxicol In Vitro. 27.
Kim SJ. et al. Curcumin stimulates proliferation of embryonic neural progenitor cells and
neurogenesis in the adult hippocampus. J Biol Chem. 283.
Lu C.et al. Design, synthesis, and evaluation of resveratrol derivatives as AB (1-42) aggregation
inhibitors, anti-oxidants, and neuroprotective agents. Bioorg Med Chem Letter. 22.
62
References for Anti-oxidants
Madrigal JL. et al. glutathione depletion, lipid peroxidation and mitochondrial dysfunction are
induced by chronic stress in rat brain. Neuropsychopharm. 2001. 24(4).
Marí M. et al. Mitochondrial Glutathione, a Key Survival Antioxidant. Antioxidants & Redox
Signaling. 2009;11(11):2685-2700.
Moline S. et al. Polyphenols in dementia. From molecular basis to clinical trials. Life Sci. 2016
Sep 15;161:69-77.
Morris G. et al. The glutathione system: a new drug target in neuroimmune disorders. Mol
Neurobiol. 2014 Dec;50(3):1059-84.
Perez-Hernandez J. et al. A potential alternative agent for neurodegenerative diseases:
Phytodrugs. Oxidative medicine and cellular longevity. 2016.
Pocernich CB. et al. Nutritional approaches to modulate oxidative stress in Alzheimer’s
disease. Curr Alz Res. 2011 Aug;8(5):452-69.
Rangarajan P et al. Role of dietary phenols in mitigating microglia mediated
neuroinflammation. Neuromolecular Med 2016 Sep.
63
References for Anti-oxidants
Saitoh Y, et al. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon
mutagenicity, genotoxicity, and subchronic oral toxicity. Toxicology and Industrial Health.
2010. 26(4):203-216.
Scapaggnini G. et al. Modulation of Nrf2/ARE pathways by food polyphenols: A nutritional
neuroprotective strategy for cognitive and neurodegenerative disorders. Mol Neurobiol. 2011.
44:192-201.
Vacca RA. et al. Plant polyphenols as natural drugs for the management of Down Syndrome
and related disorders. Neurosci Biobehav Rev. 2016 Dec;71:865-877.
Vonder Haar C. et al. vitamins and nutrients as primary treatments in experimental brain
injury: Clinical implications for nutraceutical therapies. Brain Res. 2016 Jun 1:1640(Pt A:114-29
Yang C et al. Curcumin upregulates transcription factor Nrf2, HO-1 expression and protects
rat brains against focal ischemia. Brain Research. 2009. 1282:133-141.
Zaky A. et al. A combination of resveratrol and curcumin is effective against Aluminum
Chloride induced neuroinflammation in rats. J. Alzheimer’s Dis. 2017 Feb 7.
64
References for Glutathione
Cooke RW. Et al Reduction of oxidative stress marker in lung fluid of preterm infants after
administration of intra-tracheal liposomal glutathione. Bio Neonate. 2005;87(3):178-80.
Hauser AR. Et al. Randomized, double-blind, pilot evaluation of intravenous glutathione in
Parkinson's disease. Mov Disord. 2009 May 15;24(7):979-83. doi: 10.1002/mds.22401.
James J. Et al. Am J Clin Nutr 2004;80:1611-161
Kern JK. Et al. A clinical trial of glutathione supplementation in autism spectrum disorders. Med
Sci Monit. 2011; 17(12): CR677–CR682
Madrigal JL. Et al. glutathione depletion, lipid peroxidation and mitochondrial dysfunction are
induced by chronic stress in rat brain. Neuropsychopharm. 2001. 24(4).
Marí M. et al. Mitochondrial Glutathione, a Key Survival Antioxidant. Antioxidants & Redox
Signaling. 2009;11(11):2685-2700.
Morris G. et al. The glutathione system: a new drug target in neuroimmune disorders. Mol
Neurobiol. 2014 Dec;50(3):1059-84.
Sechi G. Et al. Reduced intravenous glutathione in the treatment of early Parkinson's disease
Prog Neurospychopharm Biol Psych. 1996 Oct;20(7):1159-70.
Sinha R. Et al. Oral supplementation with liposomal glutathione elevates body stores of
glutathione and markers of immune function. European Journal of Clinical Nutrition advance
online publication, 30 August 2017; doi:10.1038/ejcn.2017.132. (Tri-Fortify™ study)
65
References for Molecular Hydrogen
Dohi, K., et al., Molecular Hydrogen in Drinking Water Protects against Neurodegenerative
Changes Induced by Traumatic Brain Injury. PLoS One, 2014. 9(9): p. e108034.
Domoki, F., et al. Hydrogen is neuroprotective and preserves cerebrovascular reactivity in
asphyxiated newborn pigs. Pediatric Research. 2010. 68(5): p. 387-392.
Eckermann, J.M., et al. Hydrogen is neuroprotective against surgically induced brain injury.
Medical Gas Research. 2011. 1(1): p. 7.
Ichihara, M., et al., Beneficial biological effects and the underlying mechanisms of molecular
hydrogen - comprehensive review of 321 original articles. Med Gas Res, 2015. 5: p. 12.
Molecular hydrogen foundation: www.molecularhydrogenfoundation.org
Ohno, K. et al. Molecular hydrogen as an emerging therapeutic medical gas for
neurodegenerative and other diseases. Oxidative Medicine and Cellular Longevity, 2012.
2012: p. 353152.
Ohta, S., et al. Molecular hydrogen as a preventive and therapeutic medical gas: initiation,
development and potential of hydrogen medicine. Pharmacol Ther, 2014.
Saitoh Y, et al. Biological safety of neutral-pH hydrogen-enriched electrolyzed water upon
mutagenicity, genotoxicity, and subchronic oral toxicity. Toxicology and Industrial health.
2010. 26(4):203-216.
Wang, C., et al., Hydrogen-rich saline reduces oxidative stress and inflammation by inhibit of
JNK and NF-kappaB activation in a rat model of amyloid-beta-induced Alzheimer's disease.
Neuroscience Letters, 2011. 491(2): p. 127-32.
Yu, J., et al., Molecular hydrogen attenuates hypoxia/reoxygenation injury of intrahepatic
cholangiocytes by activating Nrf2 expression. Toxicol Lett, 2015. 238(3): p. 11-19.
66
References: Neuropathology
Banks WA. et al. Blood to brain transport of interleukin links the immune and central nervous systems. Life Sci. 1991. 48. L117-L121.
Black ML. et al. Air pollution: mechanisms of neuroinflammation and central nervous system disease. Trends in Neurosciences. 2009 Sept Vol 32(9).
Budzyniski J. et al. Brain-gut axis in the pathogenesis of Helicobacter Pylori infection. World J Gastroenterol. 2014 May 14:20(18).
Daulatzai, MA. et al. Chronic functional bowel syndrome enhances gut-brain axis dysfunction, neuroinflammation, cognitive impairment and vulnerability to dementia. Neurochemical Research. 2014 April Vol 39(4).
Deretzi G. et al. Gastrointestinal immune system and brain dialogue implicated in neuroinflammatory and neurodegenerative diseases. Current Molecular Medicine. 2011 Nov. Vol 11(8).
D’Mello F. et al. Cytotoxic effects of environmental toxins in human glial cells. Neurotox Res.2017 Feb.
El-Ansary A. et al. Neuroinflammation in autism spectrum disorders. J. of Neuroinflammation. 2012, 9:265.
Gutierrez EG. et al. Murine tumor necrosis factor alpha is transported from blood to brain in the mouse. J. Neuroimmunol. 47, 169-176
67
References: Neuropathology
Kern JK. et al. Relevance of Neuroinflammation and Encephalitis in autism. Frontiers in
Cellular Neuroscience. 2016 Jan.
Li X. Ee al. Elevated immune response in the brain of autistic patients. J Neuroimmunol 2009
207:111-116.
Madore C. et al. Neuroinflammation in autism: Plausible role of maternal inflammation,
dietary omega 3, and microbiota. Neural Plasticity. Volume 2016. Onyango IG. Et al.
Mitochondria in the pathophysiology of Alzheimer’s and Parkinson’s diseases. Front Biosci
(Landmark Ed). 2017 Jan1; 22:854-872.
Morales I. et al. Neuroinflammation in the pathogenesis of Alzheimer’s disease: A rational
framework for the search of novel therapeutic approaches.
Pietikainen A. et al. Cerebrospinal fluid cytokines in Lyme neuroborreliosis. J.
Neuroinflammation. 2016 Oct 18: 13(1).
Teeling JL. et al. Systemic infection and inflammation in acute CNS injury and chronic
neurodegeneration: Underlying mechanisms. Neuroscience. 2009. 158, 1062-1073.
Vargas AL. et al Neuroglial activation and neuroinflammation in the brain of patients with
autism. Ann Neurol. 2005 Jan;57(1):67-81.
Vasant MS. et al. Cellular and molecular mediators of neuroinflammation in the pathogenesis
of Parkinson’s disease. Hindawi Pub. Corporation. Mediators of Inflammation 2013.
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