MTHFr, Methylation and Metals

MTHFr, Methylation
and Metals
Dr. Amy A. Yasko
Ph.D., ND, NHD, AMD, HHP, FAAIM
“What do schizophrenia, diabetes and autism have in
common? The answer is that many different factors act
together to influence their development. As well as
fundamentals like age and gender, other genetic and
environmental factors…may play a role in the onset of
these so-called multifactorial diseases.”
Multifactorial Diseases:Choose your targets
BIOPEOPLE, Summer 2004
Multifactorial Disease
•Environmental
•Genetic
•Infectious
•Stress
DISEASE
Predisposing Factors That Increase
Susceptibility to Autism
MTHF & COMT Allelic Variations
Number of Glutamate Receptors (total “Excitotoxin” level)
Prior Underlying Streptococcal Infection
Heavy Metal Burden
Chronic Viral Infection
Sex, Blood Type, HLA Type
DPT Vaccine
Viewing Order
• Neurological Inflammation Tape
• Putting It All Together 2 part tape
• Boston DVDs
Predisposing Factors That Increase
Susceptibility to Autism
• MTHF & COMT Allelic Variations •
Number of Glutamate Receptors (total “Excitotoxin” level)
Prior Underlying Streptococcal Infection
Heavy Metal Burden
Chronic Viral Infection
Sex, Blood Type, HLA Type
DPT Vaccine
Methylation
• Importance of methylation
• Pathway
• What we can do about it
Methylation
Methyl groups – CH3
H
H
C
H
Bound to DNA, enzymes, vitamins
In many cancer cells, inappropriate
methylation – the attachment of methyl (CH3)
groups to DNA’s cytosine bases – can silence
genes that supress tumor growth.
Methylation
•
•
DNA synthesis
•
Megaloblastic anemia
•
T cells
•
Intestinal mucosa
Involved in DNA regulation
•
Host
•
Viral
•
Myelination and pruning
•
Proper immune response to i.e. TB
•
Membrane fluidity, phospholipid methylation
•
Enzymatic reactions requiring methylation
•
Melatonin
•
Neurotransmitter levels : dopamine,norepinephrine
•
Tryptophan methylation: serotonin,
Methylation is related to neurotransmitter levels; methylation of
intermediates in tryptophan metabolism can affect the levels of
serotonin. Intermediates of the methylation pathway are also shared
with the pathway involved in dopamine synthesis. Consequently,
imbalances in the methylation pathway will also affect the
neurotransmitter dopamine. In addition to its direct role as a
neurotransmitter, dopamine is involved in methylating phospholipids
in the cell membranes. Membrane fluidity is important for a variety of
reasons including proper signaling of the immune system as well as
protecting nerves from damage. The building blocks for DNA and
RNA require the methylation pathway. Without adequate DNA and
RNA it is difficult for the body to synthesize new cells. This would
result in a decreased level of new T cell synthesis. De novo T cell
synthesis is necessary to respond to viral infection, as well as for
other aspects of the proper functioning of the immune system.
Metals
myelination
methylation is necessary for myelination
Metals
myelination
remyelination
lack of methylation
methylation
and
metals
myelination
Without myelin, axons will continue
to grow and pruning will be
compromised.
Serotonin
5-HT; 5-hydroxytryptamine
Melatonin
N-acetyl-5-methoxytryptamine
DNA Methylation
“DNA methylation may maintain the large amount of
non-coding DNA in an inert state.”
“This process would help prevent the transcription of
large parts of the genome… INSERTED VIRAL
SEQUENCES.”
“…consequences of loss of methylation… could cause
the potentially harmful expression of inserted viral
genes.”
New England Journal of Medicine, November 20, 2003
Methylation in Arsenic Detoxification
Arsenite methylation by methylvitamin B12 and glutathione
does not require an enzyme.
Toxicol Appl Pharmacol. 1999 Feb 1;154(3):287-91.
Zakharyan RA, Aposhian HV.
Department of Molecular and Cellular Biology, The University of Arizona, Tucson, Arizona, 85721-0106, USA.
Although inorganic arsenic is methylated enzymatically by arsenic methyltransferases, which
have been found in many mammalian livers, the detection of such enzymes has not been
successful in surgically removed human livers. Results of the present experiments
demonstrated that methylvitamin B12 (methylcobalamin, CH3B12) in the presence of thiols
and inorganic arsenite can produce, in vitro, substantial amounts of monomethylarsonic acid
(MMA) and small amounts of dimethylarsinic acid (DMA) in the absence of enzymes.
Furthermore, this nonenzymatic methylation of inorganic arsenite by CH3B12 was increased
substantially by the presence of dimercaptopropanesulfonate (DMPS) and/or sodium selenite.
The actions of DMPS and selenite together were additive. The methylation by CH3B12 was
neither inhibited nor stimulated by human liver cytosol. Since the amount of MMA produced
by the in vitro system described in this study was not small, these results emphasize the need
for a properly designed nutritional study in humans exposed to inorganic arsenic as to the
relationship between vitamin B12, selenium, and the metabolism of carcinogenic inorganic
arsenic. Copyright 1999 Academic Press.
Methyl-donor deficiency due to chemically
induced glutathione depletion
Cancer Research, Vol 56, Issue 5 995-1005, Copyright © 1996 by American Association for Cancer Research
K Lertratanangkoon, RS Orkiszewski and JM Scimeca
Department of Pharmacology, University of Texas Medical Branch, Galveston 77555-1031, USA.
•
Dietary deficiency of methionine (Met) is known to deplete cellular
Met and cause DNA hypomethylation, but depletion of Met and
impairment in methylation due to chemically induced glutathione
(GSH) depletion has escaped recognition.
•
These results provide direct evidence that depletion of GSH leads to
Met depletion and also injures the methylation processes.
•
In animal models, levels of glutathione remain constant in females
who have suffered a brain injury, but drop by as much as 80 percent
in males with the same injury. When glutathione levels drop, brain
cells die much more quickly. This suggests that boys with brain
injuries may require different life-saving treatments than girls.
(Researchers Find Brain Cells Die Differently in Males and Females; Pediatric Academic
Societies Press release; 21-Apr-2004 )
Dennis Grayson, Ph.D.
Associate Professor of Molecular Biology and Neuroscience
Neuropsychiatric Institute University of Illinois at Chicago
•
Down-regulation of reelin and GAD67 expression in post-mortem brains of patients
diagnosed with schizophrenia and not in post-mortem material obtained from other
psychiatric patients (Guidotti et al., 2000).
•
To date, reelin and GAD67 mRNA and protein levels are reduced by approximately
50% in every cortical area, in hippocampi and in cerebella of postmortem brains
obtained from patients diagnosed with schizophrenia. In these same samples, there
were no changes in the levels of GAD65 immunoreactivity and mRNA that are
expressed in the same neurons that express reelin and GAD67. This suggests the
possibility that the genes encoding reelin and GAD67 may be coordinately regulated
and that there may be a defect in the regulation of the promoters of each gene that
compromises expression.
•
Based on data obtained thus far, we suggest that methylation represents a switch
that can be used to turn off reelin expression under appropriate conditions. We are
addressing whether this may also be operative in the regulation of GAD67 and
GAD65. The role that methylation plays in regulating gene expression in the nervous
system is still under explored. We know that alterations in methylation can result in
mental retardation. Mutations that occur in methyl CpG binding proteins have drastic
consequences that occur postnatally.
The link between mental disorders and methylation aberrations
indicates that DNA methylation plays a vital role with regard to
normal functioning of the central nervous system (Robertson and
Wolffe, 2000 ). A further indication for an important role of
methylation in the brain is the observation of high levels of
neuronal methyltransferase (Goto et al., 1993 ). One of the first
mental disorders to be linked to errors in methylation was fragile-X
syndrome, a predominantly male form of mental retardation.
Patients with this disorder display an increase in methylation at the
CpG island upstream of the FMR1 (fragile-X mental retardation)
gene coupled with a decrease in FMR1 expression (Robertson
and Wolffe, 2000 ). An additional mental disorder linked to
alterations in methylation is Rett syndrome, an X-linked disorder
responsible for a predominantly female form of mental retardation.
This appears to stem from a mutation in the gene that encodes the
methylcytosine-binding protein MeCP2 (Nan et al., 1997 ).
Furthermore, Prader-Willi and Angelman syndromes, both
characterized by severe mental deficits, are linked to alterations
in the methylation patterns of a differentially methylated region
within the SNRPN promoter/exon1 region on the paternal and
maternal alleles, respectively (Shemer et al., 2000 ).
Beckwith-Wiedemann syndrome (BWS) is an example of a
developmental disorder due to alteration of methylationregulated imprinting mechanisms. BWS is characterized by
developmental growth disorders, which, in some cases, is
accompanied by increased expression of Igf2 (Issa and Baylin,
1996 ). Igf2 is typically a paternally expressed gene, but loss of
imprinting may be caused by abnormal patterns of methylation
(Maher and Reik, 2000 ). Furthermore, certain
methyltransferases may be essential in embryonic development;
a homozygous null mutation of de novo methyltransferase
Dnmt1 results in embryonic lethality in mice (Bestor, 2000 ).
Methylation-dependent T cell immunity to Mycobacterium
tuberculosis heparin-binding hemagglutinin.
Temmerman S, Pethe K, Parra M, Alonso S, Rouanet C, Pickett T, Drowart A, Debrie AS, Delogu G, Menozzi
FD, Sergheraert C, Brennan MJ, Mascart F, Locht C.
Nat Med. 2004 Sep;10(9):935-41. Epub 2004 Aug 08.
• Methylation of the Mycobacterium tuberculosis
heparin-binding hemagglutinin (HBHA) by the
bacterium is essential for effective T cell
immunity to this antigen in infected healthy
humans and in mice.
• Post-translational modifications of proteins may
be crucial for their ability to induce protective T
cell-mediated immunity against infectious
diseases such as tuberculosis.
Methylation and Fragile X
•
In females methylation is used regularly to solve a problem. Men have only one X
chromosome and women have two. As a result, female cells might be expected to
make twice as much protein from the information on X chromosomes as males do.
Instead, women's cells randomly pick one of the X chromosomes and turn it off by
methylation. Thus both males and females have one working X chromosome in each
cell and as a result, one working unit of all the genetic information on the X
chromosome.
•
However, in fragile X syndrome, methylation is involved in causing the disease. Near
the Fragile X Mental Retardation 1 gene (FMR1) is a regulatory site called a CpG
island. In most people, the site is not methylated. As a result, the cell can use the
FMR1 gene when there is a need for Fragile X Mental Retardation Protein (FMRP).
•
In people with fragile X syndrome, the CpG island is methylated. As a result, the cell
is unable to copy the information in the FMR1 gene. Since an mRNA copy is not
made, FMRP will not be synthesized. Since there is no FMRP at the time and place
it is needed, the characteristics of fragile X syndrome are set in motion.
•
Having more than 230 CGG repeats sets in motion methylation of part of the FMR1
gene. The methylation stops the synthesis of FMRP and the absence of FMRP
causes fragile X syndrome. We do not know why having too many CGG repeats
triggers methylation.
Fragile X
•
•
•
•
DNA methylation
FMRP is an RNA binding protein
Excessive glutamate
Decreased pruning
Friedrichs Ataxia
• DNA methylation
Reelin
• DNA methylation
• Decreased gaba
• Relationship to Schizophrenia
Reelin
• Methylation of the reelin gene is used to
regulate its activity.
• There are 100 potential sites for
methylation on the reelin gene.
• Lack of methylation may lead to the extra
long versions of the reelin protein found by
Kellers group.
Nucleic Acids Research July 2002, page 2930, PNAS March 29, 2000, page 3556
On the epigenetic regulation of the
human reelin promoter.
Chen Y, Sharma RP, Costa RH, Costa E, Grayson DR.
Nucleic Acids Res. 2002 Jul 1;30(13):2930-9.
• Reln mRNA and protein levels are reduced by
approximately 50% in various cortical structures of postmortem brain from patients diagnosed with
schizophrenia or bipolar illness with psychosis.
• These findings indicate that one determinant responsible
for regulating reelin expression is the methylation status
of the promoter. Our data also raise the interesting
possibility that the down-regulation of reelin expression
documented in psychiatric patients might be the
consequence of inappropriate promoter
hypermethylation.
Methylation
Reelin
Reelin
GAD enzyme
Angelman Syndrome
• DNA methylation
• UBE3A gene
• UBE3A, "ubiquitin protein ligase E3A
• The UBE3A gene provides instructions for
making an enzyme called ubiquitin protein ligase
E3A. This enzyme is involved in targeting other
proteins to be broken down (degraded) within
cells.
• Leads to the specific degradation of proteins
through the ubiquitin-dependent proteolysis
system.
• Protein degradation is a normal process that
removes damaged or unnecessary proteins and
helps maintain the normal functions of cells.
The lack of ubiquitination could
lead to failure to degrade
these proteins or to other
functional alterations of target
proteins.
Adenylsuccinate
Lyase Mutation
• Inability to synthesize DNA
• Inability to synthesize RNA
Cerebral Folate Deficiency
• Decreased methylation
Effect of methylation on
Metallothionein genes
• “Differences in methylation may account
for the differential susceptibility of tissues
to cadmium toxicity”
Detoxification
• Glucuronidation
• Sulfation
• Methylation
• Catechol O methyl transferase (flavinoids)
• COMT
• Phenol O methyltransferase(phenols)
• Thiol methyltransferase (IBD)
At least 15% of the general population has a
genetic enzyme defect (C-to-T mutation of
nucleotide 677 of the MTHFr gene) that causes
elevated homocysteine. High levels of
homocysteine are correlated with heart disease, as
well as with Alzheimer’s disease. Moreover, higher
risks of neural tube malformations have been
attributed to this mutation. An additional genetic
change in the MTHFr gene, known as A1298C,
also results in a lowered enzymatic activity. It is
essential when screening, to use a test that looks
for BOTH of these mutations, the C677T and the
A1298C.
Saliva and blood tests are available to determine if
you have this mutation. According to Dr. Richard
Kunin up to 80%-90% of the patients he sees carry
one or the other of these MTHFr mutations. In Dr.
Yasko’s practice, she has seen an exceedingly
high correlation between children with this
mutation and autism and ADD, ADHD. The
pathways involved with this mutation are
understood, and nutritional supplements are
available that bypass the genetic defect.
(Presentation: Vitamin Related Mutations, Jan.,
2004).)
Case study
•
•
•
•
Severely autistic
MTHFr
Negative provoked urine
RNA based protocol with EDTA
Provoked urine tests do not
always reflect the actual body
burden of heavy metals,
especially in the presence of
chronic infection.
DMSA Provoked Urine
June 4, 2001
NO MERCURY
DMSA Provoked Urine
July 16,2001
NO MERCURY
DMSA Provoked Urine
August 15, 2001
NO MERCURY
DMSA Provoked Urine
February 3, 2002
NO MERCURY
“ D-Glucaric Acid marginally
low: A result lower than normal
range may be of no clinical
significance, or reflect (1) an
environment unusually free of
xenobiotics…
Mercapturic Acids Normal:
The level of mercapturic acids
in this patients urine sample is
within the normal range for
age and gender for individuals
that have not been exposed to
greater than average levels of
xenobiotics…”
Methylation Pathway
and
Supplementation
COMT
COMT is the enzyme that inactivates
dopamine and norepinephrine by adding a
methyl group to these compounds.
• COMT has an allelic variation with high activity,
which decreases dopamine
• COMT has an allelic variation with low activity,
which has less of a decrease of dopamine
• These variations in COMT may correlate with
children that are “over” or “under” methylated
Supplementation with
SAMe in the Methylation
Pathway
DMG
TMG
B6
cysteine
S-adenosyl-methionine (SAM)
Some of the important reactions in which SAM is involved are:
Methylation of DNA and RNA. DNA- and RNA-methylases use SAM
as a source of methyl groups. A major target of methylases is the 5
position of cytosine of DNA. The degree of methylation correlates
with transcriptional activity. (Globin genes, for example, are highly
methylated in non-erythroid cells but not in erythroid cells.
The conversion of epinephrine to norepinephrine is also catalyzed
by an N-methyl transferase that uses SAM. Note that because
methionine is an essential amino acid, if it is limiting, choline could
also become a nutritional requirement
Methyl groups in carcinogenesis: effects on DNA
methylation and gene expression.
Wainfan E, Poirier LA.
New York Blood Center, New York 10021.
Cancer Res. 1992 Apr 1;52(7 Suppl):2071s-2077s.
• Lipotrope-deficient (methyl-deficient) diets cause fatty
livers and increased liver-cell turnover and promote
carcinogenesis in rodents.
• In livers of rats fed a severely methyl-deficient diet
(MDD), lowered pools of S-adenosylmethionine and
hypomethylated DNA were observed within 1 week. The
extent of DNA hypomethylation increased when MDD
was fed for longer periods.
• The decreases in overall levels of DNA methylation were
accompanied by simultaneous alterations in gene
expression, yielding patterns that closely resembled
those reported to occur in livers of animals exposed to
cancer-promoting chemicals and in hepatomas.
Concerns in terms of the
potential role of thimerosal in
this pathway
• Tetrahydrofolate is required for the synthesis of
thymine and the purine bases used to produce
precursors of DNA
• Thus, Tetrahydrofolate is required for cell
division
• Blockage of thymine and purine base synthesis
by folate deficiency, or drugs that interfere with
folate metabolism, produces a decreased rate of
cell division and growth
Chemical Name: O-Mercaptobenzoic
acid
Synonyms
•Thiosalicylic acid
•O-Mercaptobenzoic acid
•NSC660640; NSC2184
AIDS# 018
266
Links to
ChemID
Plus by
CAS#
147-93-3
MW: 154.1
9
C7 H6 O2 S
H-bond
donors: 2
H-bond
acceptors:
2
PHIA
(Flexible
Bonds):
1.99
Calc. LogP
(KowWin): 2.22
Company:
Lines of Data: 2
Number of References: 1
Calc. LogP
(MDL QSAR): 2.21
Anti-HIV Enzyme data: 0
Number of References: 0
Lines of Data: 2
TB Min MIC
TB Min IC50
50 ug/mL
Number of References: 1
Classes: BENZOIC ACIDS; BENZOIC ACIDS
Lipinski: Y
Thimerosal
Molecular formula: C9H9HgNaO2S
Synonyms: Merthiolate; Ethyl [2mercaptobenzoato(2-)-O,S]-mercurate(1-)
sodium; Ethyl (2-mercaptobenzoato-S)
mercury, sodium salt; Mercurothiolate;
Merfamin; Mertorgan; Merzonin; [(ocarboxyphenyl)thio]ethylmercury sodium salt;
Sodium ethyl mercurithiosalicylate;
Thiomersalate; Thimerosal;
Ethylmercurithiosalicylic acid sodium salt;
Merthiolate sodium; elicide; o(ethylmercurithio)benzoic acid sodium salt;
merzonin sodium; SET; sodium ethylmercuric
thiosalicylate; thimerosalate; thimerosol;
thimersalate; thiomerosal; thiomersal; sodium
o-(ethylmercurithio)benzoate; ethyl(hydrogen
o-mercaptobenzoato)mercury, sodium salt;
nosemack; merseptyl; benzoic acid, 2mercapto-, mercury complex; elcide 75; ethyl
(sodium o-mercaptobenzoato)mercury; Elcide;
Ethylmercurithiosalicylate-sodium; Sodium salt
of (2-(carboxyphenyl)thio)ethylmercury;
CAS Registry Number: 54-64-8
Chemical Structure:
O-Mercaptobenzoic acid
Thimerosal
Requirement of RNA synthesis
for T Cell Activation
Thymidine=5 methyl uracil
Thimerosal
CO2Na
N
SHgCH2CH3
N
Thimerosal
CO2Na
S
NH
N
Hg
N
NH
“Viruses use a “Trojan horse” strategy in
which the victim assists the intruder. To
extract assistance from the host cell,
viruses use the detailed “inside
information” that they have acquired
during million of years of coevolution with
their hosts.”
Science Vol 304 April 9,2004
Factors that may lead to Chronic Viral Infection
•
•
•
Decreased T cell response due to MTHFr mutation that impairs DNA
synthesis needed for T cell clonal expansion
Impaired B cell response due to lack of T helper cells, and T
regulatory cells.
Further induction of IDO by interferon gamma
• Interferon gamma has been reported to increase intestinal
permeability and blood-brain permeability
•
•
•
Increased IDO, impact on self versus non self
Decreased vaccine efficiency, increased viral load
Nature of retroviruses themselves
Chronic Viral Infection
• Measles, Mumps, Rubella, HHV-6,
Herpes Zostar (Chicken Pox)
• Streptococcus, Herpes Virus, Measles Virus
use the same receptor to get into cells
• Increased susceptibility to all three
• Viruses
glutamate
• Viruses
host MT proteins
bind metals
inside virally
infected cells
Viruses as Parasites
• Induction of Metallothionein proteins by
viral infection
• Trapping of heavy metals by virus
Influenza Virus Infection Induces Metallothionein Gene Expression in the Mouse Liver and
Lung by Overlapping but Distinct Molecular Mechanisms
Kalpana Ghoshal,1 Sarmila Majumder,1 Qin Zhu,1 John Hunzeker,2 Jharna Datta,1
Manisha Shah,3 John F. Sheridan,2 and Samson T. Jacob1
Copyright © 2001, American Society for Microbiology
Mol Cell Biol. 2001 December; 21 (24): 8301–8317
DOI: 10.1128/MCB.21.24.8301-8317.2001
These results have demonstrated that MT-I
and MT-II can be induced robustly in the
liver and lung following experimental
influenza virus infection by overlapping but
distinct molecular mechanisms.
Effects of coxsackievirus B3 infection on the acute-phase protein
metallothionein and on cytochrome P-4501A1 involved in the
detoxification processes of TCDD in the mouse.
Funseth E, Pahlman M, Eloranta ML, Friman G, Ilback NG.
Sci Total Environ. 2002 Feb 4;284(1-3):37-47.
• Infection had induced MT approximately
10-fold.
• This may explain the observed changed
pattern of accumulation, excretion and
toxicity of the environmental pollutants
cadmium and TCDD during this common
virus infection.
Global impact of influenza virus on cellular pathways is mediated by both
replication-dependent and -independent events.
Geiss GK, An MC, Bumgarner RE, Hammersmark E, Cunningham D, Katze MG.
J Virol. 2001 May;75(9):4321-31.
• How viruses alter the environment within the host cell.
• Cellular response to influenza virus infection was examined
by monitoring the steady-state mRNA levels for over 4,600
cellular genes. Infections with active and inactivated influenza
viruses identified changes in cellular gene expression that
were dependent on or independent of viral replication,
respectively.
• Interestingly, several genes involved in protein synthesis,
transcriptional regulation, and cytokine signaling were induced
by influenza virus replication, suggesting that some may play
essential or accessory roles in the viral life cycle or the host
cell's stress response.
• The gene expression pattern induced by inactivated viruses
revealed induction of the cellular metallothionein genes that
may represent a protective response to virus-induced
oxidative stress.
Cellular response to conditional expression of hepatitis C virus core protein in
Huh7 cultured human hepatoma cells.
Li K, Prow T, Lemon SM, Beard MR.
Hepatology. 2002 May;35(5):1237-46 .
• Changes in gene expression profiles in
response to core expression were
determined using commercial
oligonucleotide microarrays (Affymetrix
GeneChip).
• Significant increases were observed in the
abundance of mRNA-encoding members
of the metallothionein (MT) family
Decreased methylation creates a
compromised host for the virus.
“DNA methylation may maintain the large amount of
non-coding DNA in an inert state.”
“This process would help prevent the transcription of
large parts of the genome… INSERTED VIRAL
SEQUENCES.”
“…consequences of loss of methylation… could cause
the potentially harmful expression of inserted viral
genes
New England Journal of Medicine, November 20, 2003
Receptor:
• Strep
• Measles
• Herpes
Binding of aluminium ions by
Staphylococcus aureus 893.
Bradley TJ, Parker MS.
Experientia. 1968 Nov 15;24(11):1175-6.
Aluminum interferes
with glutamate
dehydrogenase
Mercury inhibits
glutamine synthase
X
X
X
Glutamate pathway
“In the absence of glutamate, neurons are unaffected by
acute exposure to mercury, suggesting that neuronal
dysfunction is secondary to disturbances in astrocytes.”
“Coapplication of nontoxic concentrations of MeHG and
glutamate leads to the typical appearance of neuronal
lesions associated with excitotxin stimulation”
Brookes, 1992/Matyja and Albrecht, 1993
Aluminum inhibits the
activity of
acetylcholinesterase
Acetylcholinesterase Inhibition and
Neurological Inflammation
• Aluminum
• Organophosphates
• Pyridostigmine
Syndrome
• Aluminum
Tetanus Toxin
Alzheimers
Parkinson’s
ALS/Gulf War
Autism
Acetylcholinesterase Inhibition
Muscarinic Stimulation Nicotinic Stimulation
•
•
•
•
Pinpoint pupils
Blurred vision
Hypersecretion
Bladder incontinence
• Muscle twitching
• Muscle weakness
• Dilated pupils
The Autonomic Nervous System
Structure
Sympathetic Stimulation Parasympathetic Stimulation
Iris (eye muscle) Pupil dilation
Pupil constriction
Salivary Glands
Saliva production reduced
Saliva production increased
Oral/Nasal
Mucosa
Mucus production
reduced
Mucus production increased
Heart
Heart rate and force
increased
Heart rate and force decreased
Lung
Bronchial muscle relaxed
Bronchial muscle contracted
Stomach
Peristalsis reduced
Gastric juice secreted; motility
increased
Small Intestine
Motility reduced
Digestion increased
Large Intestine
Motility reduced
Secretions and motility increased
Liver
Increased conversion of
glycogen to glucose
Kidney
Decreased urine secretion Increased urine secretion
Adrenal medulla
Norepinephrine and
epinephrine secreted
Bladder
Wall relaxed
Sphincter closed
Wall contracted
Sphincter relaxed
Considerations
•
•
•
•
Use of choline, lecithin, phosphatidyl choline
Seizure activity and choline
Organophosphates (pesticides), GMO
Endosulphan pesticides (nuts) and gaba
release
Aluminum leads to stimulation of
the immune system
Effects on the PIP Signaling
Pathway
Work by Dr. Richard Deth
suggests that stimulation of
methionine synthase by
dopamine and IGF1 involves
activation of the PI3kinase
system.
xaluminumx
Biol Trace Elem
Res. 1997
Dietary nickel and folic acid interact to affect folate and methionine metabolism in the rat.
Uthus EO, Poellot RA.
United States Department of Agriculture, Agricultural Research Service, Grand Forks Human Nutrition Research Center, ND
58202-9034, USA.
Nickel caused a further increase in urinary FIGLU
Nickel caused a further decrease in SAMe
… Because of this, it is proposed that the physiological function of nickel is related to the
common metabolism shared by SAM and FIGLU. Possibly the physiological function of
nickel could be related to the tissue
concentration of 5-methyltetrahydrofolate (MTHF)
or tetrahydrofolate (THF).
Valproic acid can be used to treat seizures.
Valproic acid helps to increase reelin
There is literature to suggest that valproic acid may exacerbate measles
viral infection; subsequent research has found the combination of Valtrex
in conjunction with Valproic acid to be beneficial in treating viral infections.
Brand names for valproic acid include Depakote, Depakene,Valproate
Vitamin neurotoxicity.
Snodgrass SR.
Mol Neurobiol. 1992 Spring;6(1):41-73.
• Folates and thiamine cause seizures and
excitation when administered in high
dosage directly into the brain or
cerebrospinal fluid (CSF) of experimental
animals
Alteration of embryonic folate metabolism by valproic acid during organogenesis:
implications for mechanism of teratogenesis
C Wegner and H Nau
Neurology, Vol 42, Issue 4 17-24, Copyright © 1992 by American Academy of Neurology
Institute of Toxicology and Embryopharmacology, Free University Berlin, Germany.
• Valproic acid may inhibit glutamate
formyltransferase, the enzyme responsible
for the conversion of THF to the oxidized
forms 5-formyl and 10-formyl THF
• These changes could be explained by
VPA- mediated inhibition of transfer of the
formyl group via glutamate
formyltransferase
Supplementation
•
•
•
•
•
•
•
•
•
•
Step 1
Folipro
Intrinsic B12
Nucleotides
B complex TMG
P5P
Uridine Support
SAMe
Benfotiamine
Molybdenum(sulfite to sulfate)
• Magnesium will help protect against
aluminum effects on cellular
respiration
• Malic acid
• EDTA
Step 2 for
Metals
T
h
e
Aluminum (ug/g Creatinine)
E200
f
f150
e
c
t100
180
120
o 50
f
35
20
19
M
e
t
a
l
R
N
0
0
6/18/03
6/17/03
0
7/10/03
7/3/03
0
7/24/03
7/17/03
Safe Range: 60
8/5/03
8/1/03
Mercury (ug/g Creatinine)
24
25
20
15
15
12
10
9.8
10
6.4
6.6
6.5
5.4
5
7.1
5.3
3.9
2.3
2.8
2.3
1.8
0
0
0
7/10/03
6/17/03
8/15/03
8/1/03
10/1/03
9/3/03
Safe Range: 5
Lead (ug/g Creatinine)
20
18
15
13
10
7.4
6.6
5.7
5
3.6
3.3
2.3
1.7
0.2 0 0
0
0.8 0.8
0.4 0.2
9/7/03
8/19/03
0.6
0 0
0 0 0
10/18/03
9/28/03
0 0
11/14/03
11/3/03
1
0.6
0 0 0 0 0
12/15/03
11/28/03
0 0 0
1/18/04
1/3/04
Safe Range: 5
0 0 0 0 0
3/5/04
2/7/04
1 1.1
1
0.4
0
6/1/04
4/22/04
8/4/04
0
Tungsten (ug/g Creatinine)
12
12
10
8.8
8
6.1
6
5.7
5.4
4
2
1.6
1
0.5
0
0.8
0.4 0.4
0.2 0.2
0
9/7/03
8/19/03
0.8
0.3
0
10/18/03
9/28/03
1.4
0.8
11/14/03
11/3/03
0.6
0
0
0.3
0
12/15/03
11/28/03
Safe Range: 1.5
0.3 0.3
0
1/18/04
1/3/04
0.3
0
0
Prevalence of Myocarditis and Skeletal Muscle Injury
During Acute Viral Infection in Adults
JAMA April 2003
• Patients with serologically
confirmed acute influenza viral
infection
• Creatinine levels were elevated
Creatinine in Urine
Creatinine
200
200
170
170
150
100
92
90
83
76
66
50
45
61
53
50
57
40
18
35
30
26
24 25 22
0
3/30/044/9/044/17/046/17/046/21/047/20/048/25/049/8/049/23/0410/7/04
3/23/044/5/044/12/046/1/046/20/047/12/048/4/048/30/049/13/049/29/04
10/12/04
Mercury Excretion in Urine
Mercury (ug/g Creatinine)
6
5.9
5
4
3
2.5
2.7
2.2
2
1.9
1.5
1.5
1
0
0.70.7
0.3
0
0
0
0
0
0
0
0
0
0
0
3/30/044/9/044/17/046/17/046/21/047/20/048/25/049/8/049/23/0410/7/04
3/23/044/5/044/12/046/1/046/20/047/12/048/4/048/30/049/13/049/29/04
10/12/04
Step 3 and
Beyond