Transcript ALS Powerpoint Presentation - chesapeakenaturalhealth.com

ALS
Paul Faust ND
Curr Opin Neurol. 2012 Oct;25(5):530-5.
Amyotrophic lateral sclerosis.
Tremendous progress has been made in the field of ALS
based on recent neuropathological and genetic discoveries.
Moreover, the role of metabolism and nutrition in the
pathogenesis of the disease is debated and may potentially
serve as a future therapeutic target.
Areas of Investigation
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Toxic Minerals
Oxidative Damage
Deficient Methylation
Mitochondrial Dysfunction
Ketogenic Diet
Toxic Minerals
Cadmium
Excessive Copper
Mercury
Lead
Excessive Manganese
Toxic Minerals:
Cadmium
Neurotoxicology. 2001 Jun;22(3):401-10.
Blood levels of toxic and essential metals
in motor neuron disease.
Toxic and essential metals have been
implicated in the pathogenesis of
sporadic motor neuron disease (SMND).
The plasma cadmium level was
significantly raised in SMND cases.
Toxic Minerals:
Cadmium
J Cell Biochem. 2006 Jun 1;98(3):577-89.
Effects of cadmium on structure and enzymatic activity of
Cu,Zn-SOD and oxidative status in neural cells.
It has been shown that mutations found in the Cu,Zn-SOD
cause 20% of the familial ALS due to its low enzyme activity.
In addition to the effect of cadmium on Cu,Zn-SOD, cadmium
was also shown to induce neural cell apoptosis.
Cadmium decreases the content of Zn(2+), changes the
conformation of Cu,Zn-SOD protein to decrease its enzyme
activity, and causes oxidative stress-induced neural cell apoptosis.
Toxic Minerals: Cadmium
Toxic Minerals:
Excessive Copper
J Neurol Sci. 2011 Apr 15;303(1-2):95-9. Epub 2011 Feb 2.
Patterns of levels of biological metals in CSF differ among neurodegenerative diseases.
We measured the levels of some biological metals: copper (Cu), iron (Fe), magnesium (Mg),
manganese (Mn), and zinc (Zn) in the cerebrospinal fluid (CSF) in patients with
neurodegenerative diseases (52 patients with amyotrophic lateral sclerosis (ALS)), 21 patients
with Alzheimer's disease (AD), and 20 patients with Parkinson's disease (PD)
These findings suggest that Cu and Zn in particular play important roles in the onset and/or
progression of ALS, AD, and PD. Therefore, Cu-chelating agents and modulators of Cu and
Zn such as metallothionein (MT) can be new candidates for the treatment of ALS, AD, and
PD
Toxic Minerals: Copper
Antioxid Redox Signal. 2009 Jul;11(7):1627-39.
A role for copper in the toxicity of zinc-deficient
superoxide dismutase to motor neurons in amyotrophic
lateral sclerosis.
The loss of zinc from SOD1 results in the remaining
copper in SOD1 to become extremely toxic to motor
neurons in culture.
Oxidative Damage:
Melatonin
Neurotox Res. 2012 Jun 28.
Melatonin Antioxidative Defense: Therapeutical Implications for Aging and
Neurodegenerative Processes.
Melatonin also enhances the antioxidant potential of the cell by stimulating the
synthesis of antioxidant enzymes including superoxide dismutase. Melatonin
preserves mitochondrial homeostasis, reduces free radical generation and protects
mitochondrial ATP synthesis
The efficacy of melatonin in preventing oxidative damage in either cultured
neuronal cells or in the brains of animals treated with various neurotoxic agents,
suggests that melatonin has a potential therapeutic value as a neuroprotective drug
in treatment of Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic
lateral sclerosis (ALS), Huntington's disease (HD), stroke, and brain trauma.
Therapeutic trials with melatonin indicate that it has a potential therapeutic value
as a neuroprotective drug in treatment of AD, ALS, and HD
Oxidative Damage: Melatonin
J Pineal Res. 2006 Nov;41(4):313-23.
Reduced oxidative damage in ALS by high-dose enteral melatonin treatment.
Amyotrophic lateral sclerosis (ALS) is the collective term for a motoneuron disease of different
etiologies, with oxidative stress as a common molecular denominator of disease progression.
We found that melatonin attenuates glutamate-induced cell death of cultured motoneurons.
In SOD1(G93A)-transgenic mice, high-dose oral melatonin delayed disease progression and
extended survival.
In a clinical safety study, chronic high-dose (300 mg/day) rectal melatonin was well tolerated
during an observation period of up to 2 yr. Importantly, circulating serum protein carbonyls,
which provide a surrogate marker for oxidative stress, were elevated in ALS patients, but were
normalized to control values by melatonin treatment. This combination of preclinical
effectiveness and proven safety in humans suggests that high-dose melatonin is suitable for
clinical trials aimed at neuroprotection through antioxidation in ALS.
Melatonin
J Pineal Res. 2012 Jun 13. doi: 10.1111/j.1600-079X.2012.01022.x.
Overexpression of melatonin membrane receptors increases
calcium-binding proteins and protects VSC4.1 motoneurons
from glutamate toxicity through multiple mechanisms.
Melatonin has shown particular promise as a neuroprotective
agent to prevent motoneuron death in animal models of both
amyotrophic lateral sclerosis (ALS) and spinal cord injuries (SCI)..
Taken together, our findings suggest that the neuroprotection
against glutamate toxicity exhibited by melatonin may depend on
MT1 and MT2 but not GPR50.
Methylation
Methylation
Dement Geriatr Cogn Disord. 2010 Jul;29(6):553-9. Epub 2010 Jul 3.
Elevated levels of methylmalonate and homocysteine in Parkinson's
disease, progressive supranuclear palsy and amyotrophic lateral sclerosis.
We found significantly elevated concentrations of Hcy (PD 15.1, PSP 15.8,
ALS 13.9, control 11.2 micromol/l) and MMA (PD 3.7, PSP 3.1, ALS 3.7,
control 1.8 mg/g) in all patient groups in comparison with controls.
Our findings might imply that Hcy and MMA are released as a
consequence of neurodegeneration regardless of the underlying cause and
serve as surrogate markers of neurodegeneration. Alternatively they might
be directly implicated in the pathogenesis of these diseases. Since elevated
levels of both Hcy and MMA are neurotoxic, further studies might
investigate the effect of vitamin therapy on disease progression.
Methylation
J Neurol Sci. 2010 Jun 15;293(1-2):102-5.
Decreased level of 5-methyltetrahydrofolate: a potential biomarker
for pre-symptomatic amyotrophic lateral sclerosis.
Several studies have reported that homocysteine (Hcy) is associated
with amyotrophic lateral sclerosis (ALS)
Folic acid is decreased at the middle to late stages of the disease.
Furthermore, we found that the level of Hcy is markedly elevated after
the motor symptoms appeared in the ALS mice.
Our study suggests that decreased 5-MTHF level may be a potential
biomarker for the early stage of the disease in the ALS mice, which may
warrant further validating study of 5-MTHF level in ALS patients.
Methylation
Genet Test Mol Biomarkers. 2012 Jul;16(7):716-21.
Gender-specific association of methylenetetrahydrofolate reductase
gene polymorphisms with sporadic amyotrophic lateral sclerosis.
Studies have revealed that elevated homocysteine levels can cause
damage to motor neurons through multiple neurotoxic mechanisms,
thus leading to the pathogenesis of amyotrophic lateral sclerosis (ALS).
One way by which homocysteine levels are increased in the body is the
consequence of methylenetetrahydrofolate reductase (MTHFR) gene
polymorphisms.
In conclusion, the evidence we provide here clearly shows that
MTHFR C677T and A1298C polymorphisms are genetic risk factors
for SALS in women in a gender-specific manner whether they are of
spinal or bulbar onset.
Methylation
Toxicol Appl Pharmacol. 2011 Mar 15;251(3):217-25.
Methyl Vitamin B12 but not methylfolate rescues a motor neuronlike cell line from homocysteine-mediated cell death.
Homocysteine is an excitatory amino acid implicated in multiple
diseases including amyotrophic lateral sclerosis (ALS).
We conclude that MeCbl is effective against homocysteine-induced cell
death in motor neurons in a ROS-independent manner, via a
reduction in caspase activation and apoptosis. MeCbl decreases Hcy
induced motor neuron death in vitro in a hybrid cell line derived from
motor neuron-neuroblastoma and may play a role in the treatment of
late stage ALS where HCy levels are increased in animal models of
ALS.
Mitochondrial
Dysfunction
Int J Neurosci. 2005 Apr;115(4):583-91.
Lactate stress testing in sporadic amyotrophic lateral sclerosis.
Mitochondrial dysfunction is frequently observed in ALS.
Mitochondrial dysfunction may result in increased serum lactate
The LST suggests mitochondrial dysfunction in half of the ALS
patients. Mitochondrial dysfunction in ALS is related to the
clinical severity of the disease
Mitochondrial
Dysfunction
Brain Res. 2006 Jan 27;1070(1):206-14.
L-carnitine suppresses the onset of neuromuscular degeneration and
increases the life span of mice with familial amyotrophic lateral sclerosis.
A mutation of the gene encoding Cu,Zn-superoxide dismutase (SOD1) has
been reported in 20% of familial cases of ALS (FALS).
L-carnitine effectively inhibits various types of mitochondrial injury and
apoptosis both in vitro and in vivo. The present study demonstrates that
oral administration of L-carnitine prior to disease onset significantly
delayed the onset of signs of disease, delayed deterioration of motor
activity, and extended life span.
More importantly, subcutaneous injection of L-carnitine increased the life
span even when given after the appearance of signs of disease.
Mitochondrial Dysfunction
PLoS One. 2012;7(4):e34776. Epub 2012 Apr 3.
Modulation of astrocytic mitochondrial function by dichloroacetate improves
survival and motor performance in inherited amyotrophic lateral sclerosis.
Mitochondrial dysfunction is one of the pathogenic mechanisms that lead to
neurodegeneration in Amyotrophic Lateral Sclerosis (ALS).
Here, we tested the disease-modifying effect of dichloroacetate (DCA), an orphan
drug that improves the functional status of mitochondria through the stimulation
of the pyruvate dehydrogenase complex activity (PDH).
Systemic DCA also decreased astrocyte reactivity and prevented motor neuron loss
in SOD1(G93A) mice. Taken together, our results indicate that improvement of the
mitochondrial redox status by DCA leads to a disease-modifying effect, further
supporting the therapeutic potential of mitochondria-targeted drugs in ALS.
Mitochondrial Dysfunction
Brain Res Bull. 2012 Sep 15;89(5-6):185-190. doi:
10.1016/j.brainresbull.2012.09.005.
Mitochondrial dysfunction in human TDP-43 transfected NSC34 cell lines and
the protective effect of dimethoxy curcumin.
TAR-DNA-binding protein of 43kDa (TDP-43) was recently found to be one of the
major disease proteins in the pathological inclusions of amyotrophic lateral sclerosis
(ALS).
Here, we show that human TDP-43 caused mitochondrial morphologic
abnormality, decrease of mitochondrial complex I activity and mitochondrial
transmembrane potential, and increased expression of mitochondrial uncoupling
protein 2 (UCP2) in human TDP-43 stably transfected NSC-34 cells
We also show that dimethoxy curcumin (DMC) could ameliorate mitochondrial
dysfunction in mutated TDP-43 stably transfected cell lines. DMC could be
potentially useful for neurodegenerative diseases linked with mutated TDP-43.
Mitochondrial Dysfunction
Mitochondria and ALS: Implications from novel genes and pathways.
Mol Cell Neurosci. 2012 Jun 15.
Misfolded SOD1 and ALS: zeroing in on mitochondria.
Amyotroph Lateral Scler. 2012 Jun;13(4):333-40.
Mitochondrial pathobiology in ALS.
J Bioenerg Biomembr. 2011 Dec;43(6):569-79.
Ketogenic Diet
BMC Neurosci. 2006 Apr 3;7:29.
A ketogenic diet as a potential novel therapeutic
intervention in amyotrophic lateral sclerosis.
The cause of neuronal death in amyotrophic lateral sclerosis
(ALS) is uncertain but mitochondrial dysfunction may play an
important role. Ketones promote mitochondrial energy
production and membrane stabilization.
SOD1-G93A transgenic ALS mice were fed a ketogenic diet
(KD) based on known formulations for humans. This is the
first study showing that diet, specifically a KD, alters the
progression of the clinical and biological manifestations of
the G93A SOD1 transgenic mouse model of ALS. These
effects may be due to the ability of ketone bodies to promote
ATP synthesis and bypass inhibition of complex I in the
mitochondrial respiratory chain.
Ketogenic Diet
Phase II Safety and Tolerability Study of High Fat/High Calorie Versus High
Calorie Versus Optimal Nutrition in Subjects With Amyotrophic Lateral
Sclerosis
Massachusetts General Hospital ClinicalTrials.gov Identifier: NCT00983983
54% vs 29% calories from fat
Weight loss is a common and severe symptom of amyotrophic lateral sclerosis
(ALS), caused both from inadequate calorie intake and an increased metabolic
rate. People with ALS are generally instructed to increase their calorie intake;
however, the ideal amount and type of calories has not been studied. Several
studies in an animal model of motor neuron disease have shown that a high
fat/high calorie diet can increase survival by as much as 38%. Mice on a high
fat diet also live longer than mice fed diets consisting of high protein or high
sugar.
Potential Tests
24 Urine Toxic Metals plus post-provocative (DMSA)
challenge
RBC Zinc
Homocysteine
MethylMalonic Acid
RBC Folate
MTHFR DNA Analysis