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The Ependyma As A Major Player in the Pathogenesis of Amyotrophic Lateral Sclerosis: A Hypothesis By Anthony G. Payne, Ph.D. Amyotrophic lateral sclerosis (ALS) is an insidious, mercilessly devastating
disorder in which motor neurons that control voluntary movement are
progressively lost while those that are involved in cognition and sensation are
spared. At this time ALS sufferers have
no scientifically validated treatment options available to them. Fifty percent
succumb within three years of symptom onset and between eighty and ninety
percent within five years. At this point-in-time ALS has a complex, incompletely understood
etiology. Approximately 5- 10% of
cases have a genetic basis (familial ALS or fALS), with the remainder having no
clearly discernible cause. The best that can be said is that ALS is very likely
a multifactorial disorder triggered by any number of exposures such as
environmental toxicants, either alone or in combination with specific genetic
factors). This is underscored by the fact that an approximately two-fold
increase in the risk of developing ALS appeared among military personnel
deployed to Southwest Asia during the Gulf War (Aug 1990-July 1991) compared to
non-deployed personnel. Once the ALS disease process is underway, there are a number of
pathogenic mechanisms that are felt to bring about the cellular dysfunction and
apoptosis in motor neurons that are characteristic of the disease: (1)
Mitochondrial
dysfunction involving, in part, oxidative stress. (2)
Excitotoxicity due, in part,
to a down regulation of motor neuron glutamate transporters. (3)
A loss of calcium
homeostasis in motor neurons. (4)
Disrupted protein
synthesis and processing. (5)
Altered neuronal
cytoskeletal function and axonal transport. (6)
Dysfunction of
astrocytes and glial cells that support the CNS in general, as well as motot
neurons. Current therapeutic intervention is aimed at modulating the
various pathogenic processes. Research is ongoing and involves such things as
use of intravenous (IV) Ceftriaxone to upregulate glutamate
transporter genes and protein expression in motor neurons. Hypothesis It is proposed by the author that at least some cases of ALS arise
due to defective specialized neuroglial cells called ependymal cells,
especially modified ependymal cells called choroidal cells that are involved in
the synthesis and circulation of cerebrospinal fluid and maintenance of the
blood-CSF barrier. These cells may arise, at least in part, as the end result
of deleterious mutations or possibly epigenetic influences. As a result of
these cellular defects in the choroidal cells, cerebrospinal fluid is
synthesized that is laden with compounds that are neurotoxic, especially with
respect to motor neurons, as well as rich in inflammatory cytokines and such.
It is the circulation of this aberrant CSF that brings some (and in some
instances perhaps all) of the pathogenic features that characterize some cases
of ALS. Support for this hypothesis comes from two sources: (1)
Direct: Published
studies that show that CSF taken from ALS patients induces neurodegeneration
characteristic of ALS in lab animals. (2)
Indirect: Seeming
retardation in disease progression in four (4) ALS patients who have been
following a regimen that modulates neurodegenerative processes shown to result
when CSF from ALS patients is administered to lab animals and used in cell
cultures. Hypothesis Support -
Studies A.
In a lab study conducted
in India, motor neurons and spinal cord neurons in culture were exposed to CSF from
20 ALS patients and 20 controls. The “Exposure of cells
to ALS-CSF drastically decreased the survival rate of motor neurons to
32.26+/-2.06% whereas a moderate decrease was observed in case of other spinal
neurons (67.90+/-2.04%). In cultures treated with disease control CSF, a small
decrease was observed in the survival rate with 80.14+/-2.00% and 90.07+/-1.37%
survival of motor neuron and other spinal neurons respectively.” The
die-off of spinal cord cells exposed to CSF from ALS patients was linked to
elevation of intracellular calcium, while that of motor neurons to
“activation of glutamate receptors, the AMPA/kainate receptor playing the
major role.”Sen
I, Nalini A, Joshi NB, Joshi PG. B.
“CSF was injected
intrathecally into three-day-old rat pups and subsequently the ultrastructural
changes in the motor neurons were studied after 48 h, 1, 2 and 3 weeks. We
observed that ALS-CSF causes fragmentation of the Golgi apparatus in a
considerable number of motor neurons in the spinal cord. This was further
confirmed when motor neurons were stained with an antibody against a medial
Golgi protein (MG160). Thus, we suggest that the putative toxin(s) present in ALS-CSF
may cause impairment in the protein processing leading to motor neuron death.
“ Ramamohan
PY, Gourie-Devi M, Nalini A, Shobha K, Ramamohan Y, Joshi P, Raju TR.
C.
“...
earlier studies have shown that cerebrospinal fluid (CSF) of amyotrophic
lateral sclerosis (ALS) patients causes death of motor neurons, both in
in-vitro as well as in-vivo. There was an aberrant phosphorylation of
neurofilaments in cultured spinal cord neurons of chick and rats following
exposure to CSF of ALS patients (ALS-CSF). Other features of neurodegeneration,
such as swollen neuronal soma and beading of neurites were also observed. In
neonatal rat pups exposed to ALS-CSF, we observed phosphorylated neurofilaments
in the soma of spinal motor neurons in addition to the increased lactate
dehydrogenase activity and reactive astrogliosis. The present study examines
the effect of ALS-CSF on the expression of glial glutamate transporter (GLT-1)
in embryonic rat spinal cord cultures as well as in spinal astrocytes of
neonatal rats. Immunostaining suggested a decrease in the expression of GLT-1
by astrocytes both in culture and in-vivo following exposure to ALS-CSF. Our
results provide evidence that toxic factor(s) present in ALS-CSF depletes GLT-1
expression. This could lead to an increased level of glutamate in the synaptic
pool causing excitotoxicity to motor neurons, possibly by triggering the
'glutamate-mediated toxicity-pathway'. Shobha
K, Vijayalakshmi K, Alladi PA, Nalini A, Sathyaprabha TN, Raju TR. D.
“In
the present study we show that there is an increased number of astrocytes
intensely immunoreactive for glial fibrillary acidic protein (GFAP) in the gray
matter of the spinal cords of neonatal rats exposed to ALS CSF. There is also
increased expression of GFAP in the astrocytes of the white matter of neonatal
rat spinal cords exposed to ALS CSF. Western blot analysis also confirmed the
increased expression of GFAP. Accordingly, our study provides for the first
time a clear evidence for the pathological response of glia to the circulating
toxic factor(s) in the CSF of ALS patients.” Shahani
N, Nalini A, Gourie-Devi M, Raju TR. There are other studies, most cell
culture or animal, which directly or indirectly indicate that the CSF of ALS
patients contains compounds that are neurotoxic, inflammatory and proinflammatory,
and otherwise contributory to pathogenic mechanisms common to ALS. The impact of these CSF compounds can be
summarized briefly as follows: (1)
Intracellular
calcium is elevated in spinal cord neurons. (2)
Glutamate
levels rise and receptors are activated in motor neurons. (3)
Some
appear to lower quinine reductase levels in motor neurons and possibly
astrocytes, which results in increased glutamate influx. (4)
Mitochondrial
dysfunction occurs and with this compromised motor neuron energetics. (5)
Neuroinflammation
increases. (6)
Antioxidant
defenses such as glutathione are increasingly at risk of depletion or depleted. Some of these effects overlap those of
other players, both genetic and non-genetic, in ALS. As such, it is likely that
therapeutic intervention with respect to modulating synthesis of neurotoxic,
etc. compounds in the CSF or their impact on spinal cord and motor neurons, moderates
the impact of these other players. This aside, it follows that if some or
most nonfamilial ALS patients owe at least part of their condition to damage
wrought by various neurotoxic, inflammatory and proinflammatory, etc. compounds
in their CSF, dietary, pharmacologic and nutraceutical measures that lower or
otherwise modulate the synthesis of these substances or attenuate their impact
on motor neurons will slow disease progression and prolong lifespan. With this in mind, the author tooled
together just such a regimen (2005 with subsequent modifications) consisting
of: CoQ10
(Ubiquinone/ubiquinol):
Rationale for use – CoQ10 appears compromised in ALS. Dose: 200 mgs.
every 2 hours during the day (1200 mgs daily) Noni juice or capsules – Rationale for use: Contains a
potent quinone reductase inducer – QR reduces glutamate toxicity in
cells. Dosage: Juice to be drunk liberally all day long. Capsules – 1
every 2 hours during the day and 1-2 capsules one hour to one-half hour before
bedtime. Tumeric Extract Tablets or
Capsules –
Rationale for use: Quinone reductase inducer in astrocytes (Lowers
glutamate). Dose: 1 (.05 gram) tablet
every two hours during the day and 1-2 tablets prior to bedtime. DEPRENYL:
According to a 1994 animal study, “CSF samples from
ALS and non-ALS neurological patients were injected into the spinal
subarachnoid space of 3-day-old rat pups, followed by a single dose (0.01 mg/kg
body weight) of (-)-deprenyl, administered 24 h after CSF injection. After a
further period of 24 h, the rats were sacrificed and the spinal cord sections
were stained with antibodies against phosphorylated neurofilament (NF, SMI-31
antibody) and glial fibrillary acidic protein (GFAP). Activity of lactate
dehydrogenase (LDH) was also measured. (-)-Deprenyl injection resulted in a
significant (61%) decrease in the number of SMI-31 stained neuronal soma in the
ventral horn of the spinal cord of ALS CSF exposed rats. This was accompanied
by a reduction in the astrocytes immunoreactive for GFAP. There was also a
significant (35%) decrease in the LDH activity following (-)-deprenyl
treatment. These results suggest that (-)-deprenyl may confer neuroprotection
against the toxic factor(s) present in ALS CSF.” Shahani
N, Gourie-Devi M, Nalini A, Rammohan P, Shobha K, Harsha HN, Raju TR. Dose:
Discretionary with each patient’s physician. Use of patches or oral forms
(Pills, tablets or liquid). The typical daily dose was 12 mgs/daily. IV Glutathione: Rationale – depleted in many ALS
patients or at risk of becoming so. The intravenous (IV) dose is determined by
each patient’s physician. During 2007 a patented oral form of glutathione
became available, one that is absorbed through the oral mucosa and resists
breakdown until it reaches the CNS (Th-Queen from PREVAGEN (Aequorin) – Rationale for use:
Prevents calcium influx and resultant toxicity in neurons. Dose: One twenty
milligram (20 mg) capsules every 2 to 3 hours during waking hours and one to
two (1-2) capsules 30-60 minutes before retiring for the night. Aequorin became available commercially
during 2007 and was added to the regimen at that time. Lithium – Rational for use: Glutamate
modulation in neurons. Dose: 250 mgs. to 600 mgs Lithium carbonate daily
(Dosage determined by each patient’s neurologist or primary care
physician). Lithium was added to the regimen during 2007. Diet: Medium Chain Triglycerides Diet.
Rationale: There are many reasons the ketogenic or MCT diets might be of benefit
to ALS patients, not the least of which is the fact they tend to increase
glutamate transporter gene expression. Ketogenic
& MCT Diet (Epilepsy website) Hypothesis
Support – Clinical Responses (n=4) Four individuals diagnosed with nonfamilial
ALS (3 male, 1 female, ages 35-52) adopted the regimen outlined above beginning
during 2005, all with their primary care physician or neurologist’s
participation (Note that Prevagen was introduced during 2007 when it became
available. Lithium was likewise added during 2007). All four experienced
disease progression, however when compared to age- and disease matched
controls, the degree of progression is decidedly less. One (male) patient noted
that “Every single ALS patient diagnosed at the same time I was
(diagnosed) is now dead or on a respirator. I am still walking, talking, eating
and living my life. I’ve lost some functioning in my hands and arms, but
this is not so great as to rob me of doing things I need to do like driving my
car”. While the responses of these six is far
from definitive and cannot be called rigorous in the scientific sense, it is
suggestive and offers a very tentative confirmation of the hypothesis put
forward. A greater degree of confirmation will
come when, for example, the choroidal cells in the brains of ALS are replaced
in whole or part by healthy counterparts produced from stem cells. In
accordance with this hypothesis, it is expected that synthesis and circulation
of a healthy CSF will result in a significant degree of disease progression or
even disease arrest. See also this variation of the regimen cited in this paper: Retarding ALS Progression
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