Regimen to promote neuroprotection and encourage
(plus a compendium of resources and promising
adjunctive therapeutic agents for Multiple Sclerosis and other neurological
diseases & disorders)
Printable PDF format version
Dr. Anthony G. Payne
Suggested regimen to help quell inflammation
and promote nerve repair in various neurodegenerative and neuroinflammatory
diseases and disorders
Diet: Paleolithic (“Stone Age”).
30% or more protein (2:1 ratio of omega-3 to omega-6 fatty acid containing
fish, game meat, etc., 1:1 Magnesium to Calcium intake, low sodium-high
potassium) 70% complex carbohydrates (Fruits and vegetables). No grains, cereals or bovine milk.
(Helpful dietary chart can be found below)
Use of curry and Tumeric powder in foods is
20 minutes before
or 1 hour after meals:
800 mgs. to 1 gram: N-acetylcysteine
1 gram of Acetyl-L-carnitine
500 mgs. to 1 gram: Taurine
500 mgs. to 1.0-1.5 grams time-released Niacinamide
50 mgs. Thiamine (B1)
50-100 mgs. R-Lipoic Acid
50 mgs. Non-toxic NDGA
T4 (Thyroid) – Check with primary care physician regarding advisability of using this
(MD or DO must monitor T4 hormone level regularly). Abstract concerning
rationale for inclusion in references section.
May be of merit -
Discuss with primary healthcare provider
Velvet Deer Antler extract
(Spray or tablets). Follow product label recommendations.
Extract Capsules (Counters glutamate neurotoxicity). Follow
product manufacturer recommendations. Abstract in reference section.
Drink magnesium rich “hard” water as often as possible: http://www.mgwater.com/list5.shtml . Also make green tea using this type of
water (See below)
Make and drink organic Japanese green tea 2-3 times daily http://www.o-cha.com/green-tea/Organic-Matcha-P300-Kaoru-Supreme-pr-16138.html -. This is one of the best, “Kaoru Supreme” Make using a magnesium rich water (See above for one source). NOTE: Author has no financial or other interest
in this firm or any commercial source listed in this free access regimen.
Glycerophosphocholine (GPC) – 1 or 2 capsules one (1) hour before or 2 hours
Phosphatidylserine (PS) – 1 softgel 3 x daily or more often.
Luteolin: The scientific evidence for the benefits of luteolin
for various neurologic challenges is beginning to accrue. One luteolin-rich
source is a product called ”Lutimax” --
(Rich in luteolin):
http://www.dragonwater.com/search.tf/tea/rooibos_tea/?z=go_rooibos_tea&gclid=CKq9g-rR6IMCFQMZIgodqzqpLw - Organic Rooibos Tea
L-Theanine Take 1
capsule with or after each meal and snack and then 2 capsules 30 minutes
before retiring at night (Theanine appears to contribute to mood modulation
and relaxation-promotion via its ability to increase GABA and dopamine)
GUIDELINES -- PALEODIET
70 % Per Day
(Green and Yellow)
Natural vanilla flavoring
30% Per Day
(Especially the high Protein Meats & such)
Carrot Juice (no
more than ｼ glass)
Red Grapes with
(if not allergic)
Wheat grass juice
filberts (not roasted or salted)
Fish (be careful
of mercury content)
0% Per Day
Monosodium glutamate or Vegetable
with increased salt or sugar
Water with heavy
can increase the toxicity of aluminum)
Resources, References, Supporting Material
http://www.stemcelltherapies.org/ms.htm - This link is to a very comprehensive
article on alternative approaches to treating MS (by Dr. David A. Steenblock,
Medical Director & CEO, Steenblock Research Institute, Research & Development Laboratory, 1064
Calle Negocio #B, San Clemente,
http://www.strokedoctor.com/ - Dr. David
A. Steenblock’s medical practice website - devoted to brain repair and
rehabilitation. Many good research papers and such posted on this website.
- Organophosphates, general.
- The Chronic and Delayed Effects of Organophosphate (OP) Poisoning
- Heavy metals toxicity
- Neurodegenerative diseases and
conditions: Causes, natural and other treatments, et cetera
Diet, supplements, abstracts, etc.
Curcumin (Diferuloylmethane) is a compound found in the Indian curry
It has been discovered that people in India have a very low incidence
of neurological diseases and researchers have attempted to find out why this
is. They have looked at the spice, tumeric,
which was known from traditional Indian medicine as an anti-inflammatory agent effective in
wound healing. Research using curcumin, the active ingredient of tumeric, in EAE, a mouse model of multiple sclerosis, has shown
that it may be of benefit to people with MS.
Curry spice may fight multiple sclerosis
The Spice of Life - Unlocking the power of
Piperin Home page
Curcuma longa (turmeric). Monograph.
Curcumin inhibiting of TNF-mediated
adhesion of monocytes to endothelial cells
Curcumin inhibiting of macrophage TNF-alpha
Effect of curcumin and capsaicin on rat
Curcumin inhibiting differentiation in
human endothelial cells
Curcumin and oxidative activity astrocyte
Regulation of IL-1 mediated MMP-9
expression in mesangial cells
Influence of piperine on curcumin in
animals and humans
Immunomodulatory activity of curcumin
J Nat Prod. 2002
Discovery of natural products from Curcuma longa
that protect cells from beta-amyloid insult: a drug discovery effort against
Park SY, Kim DS.
Program for Collaborative Research in Pharmaceutical Sciences and Department
of Medicinal Chemistry and Pharmacognosy (m/c 877), College of Pharmacy,
University of Illinois at Chicago, 60612, USA.
From Curcuma longa, two novel compounds, 4' '-(3' "-methoxy-4'
"-hydroxyphenyl)-2' '-oxo-3' '-enebutanyl
3-(3'-methoxy-4'hydroxyphenyl)propenoate (calebin-A, 1) and
1,7-bis(4-hydroxy-3-methoxyphenyl)-1,4,6-heptatrien-3-one (2), and seven
known compounds, 1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione
(demethoxycurcumin, 4), 1,7-bis(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione
1,7-bis(4-hydroxyphenyl)-1,4,6-heptatrien-3-one (8), and
1,5-bis(4-hydroxy-3-methoxyphenyl)-1,4-pentadien-3-one (9), were isolated
following a bioassay-guided fractionation scheme utilizing an assay to detect
protection of PC12 cells from beta-amyloid insult. Compounds 1, 3-5, and 7
were found to more effectively protect PC12 cells from betaA insult (ED(50) =
0.5-10 microg/mL) than Congo red (10) (ED(50) = 37-39 microg/mL).
J Neurosci. 2001
The curry spice curcumin reduces oxidative damage
and amyloid pathology in an Alzheimer transgenic mouse.
Lim GP, Chu T, Yang F, Beech W, Frautschy SA, Cole GM.
Departments of Medicine and Neurology, University
of California, Los
Angeles, Los Angeles,
Inflammation in Alzheimer's disease (AD) patients is characterized by
increased cytokines and activated microglia. Epidemiological studies suggest
reduced AD risk associates with long-term use of nonsteroidal
anti-inflammatory drugs (NSAIDs). Whereas chronic ibuprofen suppressed
inflammation and plaque-related pathology in an Alzheimer transgenic APPSw
mouse model (Tg2576), excessive use of NSAIDs targeting cyclooxygenase I can
cause gastrointestinal, liver, and renal toxicity. One alternative NSAID is
curcumin, derived from the curry spice turmeric. Curcumin has an extensive
history as a food additive and herbal medicine in India and is also a potent
polyphenolic antioxidant. To evaluate whether it could affect Alzheimer-like
pathology in the APPSw mice, we tested a low (160 ppm) and a high dose of
dietary curcumin (5000 ppm) on inflammation, oxidative damage, and plaque
pathology. Low and high doses of curcumin significantly lowered oxidized
proteins and interleukin-1beta, a proinflammatory cytokine elevated in the
brains of these mice. With low-dose but not high-dose curcumin treatment, the
astrocytic marker GFAP was reduced, and insoluble beta-amyloid (Abeta),
soluble Abeta, and plaque burden were significantly decreased by 43-50%.
However, levels of amyloid precursor (APP) in the membrane fraction were not
reduced. Microgliosis was also suppressed in neuronal layers but not adjacent
to plaques. In view of its efficacy and apparent low toxicity, this Indian
spice component shows promise for the prevention of Alzheimer's disease.
PMID: 11606625 [PubMed - indexed for MEDLINE]
J Immunol. 2002
Curcumin inhibits experimental allergic
encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT
pathway in T lymphocytes.
Natarajan C, Bright JJ.
Division of Neuroimmunology, Department of Neurology, Vanderbilt
Center, Nashville, TN 37212, USA.
Experimental allergic encephalomyelitis (EAE) is a CD4(+) Th1 cell-mediated
inflammatory demyelinating autoimmune disease of the CNS that serves as an
animal model for multiple sclerosis (MS). IL-12 is a proinflammatory cytokine
that plays a crucial role in the induction of neural Ag-specific Th1
differentiation and pathogenesis of CNS demyelination in EAE and MS. Curcumin
(1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione) is a naturally
occurring polyphenolic phytochemical isolated from the rhizome of the
medicinal plant Curcuma longa. It has profound anti-inflammatory activity and
been traditionally used to treat inflammatory disorders. In this study we
have examined the effect and mechanism of action of curcumin on the
pathogenesis of CNS demyelination in EAE. In vivo treatment of SJL/J mice
with curcumin significantly reduced the duration and clinical severity of
active immunization and adoptive transfer EAE. Curcumin inhibited EAE in
association with a decrease in IL-12 production from macrophage/microglial
cells and differentiation of neural Ag-specific Th1 cells. In vitro treatment
of activated T cells with curcumin inhibited IL-12-induced tyrosine
phosphorylation of Janus kinase 2, tyrosine kinase 2, and STAT3 and STAT4
transcription factors. The inhibition of Janus kinase-STAT pathway by
curcumin resulted in a decrease in IL-12-induced T cell proliferation and Th1
differentiation. These findings highlight the fact that curcumin inhibits EAE
by blocking IL-12 signaling in T cells and suggest its use in the treatment
of MS and other Th1 cell-mediated inflammatory diseases.
PMID: 12055272 [PubMed - indexed for MEDLINE]
ORLEANS (Reuters Health) - Preliminary
studies in rats suggest that curcumin, a compound found in the curry spice
turmeric, may block the progression of multiple sclerosis (MS).
According to researcher Dr. Chandramohan Natarajan of Vanderbilt
University in Nashville, Tennessee, rats with an MS-like illness showed
little or no signs of disease symptoms after being injected with curcumin,
while animals without the treatment went on to severe paralysis.
"We got a very good inhibition of the disease by treating with
curcumin," Natarajan told Reuters Health. He presented the findings here
Tuesday at the annual Experimental Biology 2002 conference.
No one knows what causes multiple sclerosis, in which the body's immune
system attacks the protective myelin sheath surrounding nerve fibers in the
brain and spine. Symptoms of multiple sclerosis include muscle weakness and
stiffness, balance and coordination problems, numbness and vision
Interest in the potential neuroprotective properties of curcumin rose
after studies found very low levels of neurological diseases such as
Alzheimer's in elderly Indian populations. Added to this were studies confirming
curcumin as a potent anti-inflammatory agent, effective in wound healing. And
just last fall, researchers at the University
of California, Los Angeles reported that curcumin appeared
to slow the progression of Alzheimer's in mice.
In their 30-day study, Natarajan and co-researcher Dr. John Bright gave
injections of 50- and 100-microgram doses of curcumin, three times per week,
to a group of mice bred to develop a disease called experimental autoimmune
encephalomyelitis (EAE)--an autoimmune condition used by researchers as a
model for multiple sclerosis because it also results in the slow erosion of
myelin. They then watched the rats for signs of MS-like neurological
By day 15, rats who had not received curcumin developed EAE to such an
extent that they displayed complete paralysis of both hind limbs, according
In contrast, rats given the 50-microgram dose of the curry compound
showed only minor symptoms, such as a temporarily stiff tail. And rats given
the 100-microgram dose appeared completely unimpaired throughout the 30 days
of the study.
The results didn't really surprise Natarajan. "In Asian countries,
such as India, China, who are eating more spicy foods, more yellow compounds
like curcumin...there are only very, very rare reports of MS," he
pointed out. He said the doses the rats received were roughly equivalent in
human terms to those found in a typical Indian diet.
Just how curcumin might work to thwart the progression of demyelinization
remains unclear. But the Nashville
researchers believe it may interrupt the production of IL-12, a protein that
plays a key role in signaling immune cells to launch their assault on the
Natarajan stressed that "we have to do a lot of work on this,"
including examining other potential mechanisms by which curcumin slows EAE
and, potentially, MS.
The work remains preliminary, and MS patients should follow their
doctor's advice when it comes to treating the disease. Still, Natarajan said
adding a little curry to the diet couldn't hurt. "I think using this
spice in their food could be of help," he said.
Blue Wavelength light exposure may ameliorate MS
Animal Model of Multiple Sclerosis:
・To help in research of multiple sclerosis (MS) researchers utilize an
animal model, experimental allergic encephalitis (EAE). EAE is an acute
autoimmune demyelination disease, that matches the symptomatology of MS. Guinea
pigs with EAE are reported to have a reduction of serotonin within the
central nervous system (CNS), when compared to control subjects. The
reduction of serotonin within the CNS leads to an effect on CNS serotonin
transmissions in EAE, either at the level of serotonin receptor itself, or at
the level of serotonin transmitting neurons (Scott, Cashman, and Spitler, 1982-83).
The symptoms of EAE are due to the inhibition of serotonin transmission.
In animals with EAE,
administration of L-5-hydroxytrytophan, a precursor to serotonin, reversed
the effects of impaired serotonergic transmission. Suggesting that there
might be a blockade of serotonin receptors (Scott, Cashman, and Spitler, 1982-83),
which can be overcome by the addition of a drug that increases the CNS
serotonin levels. The addition of a precursor of serotonin has such an
effect, and then the addition of antidepressant type drugs may affect
the symptoms of EAE in a positive way.・/SPAN>
Blue Light Wavelengths Increase Serotonin
Several very recent studies, most notably research from a team headed by
Dr. George Brainard at Thomas Jefferson Medical College in Philadelphia, have
identified the specific wavelengths of blue light, 446-477 nm that are
crucial in suppressing melatonin production in humans. 1 2 3 4 As Dr. Brainard notes,
"This discovery will have an immediate impact on the therapeutic use of
light for treating winter depression and circadian disorders."
Melatonin, the neurotransmitter that helps us sleep deeply through the night,
is produced from serotonin. Suppressing melatonin production raises the
levels of serotonin in our brains. This is the key goal of therapeutic
bright light treatment. This neurological pathway entrains our
circadian rhythm to be awake during the day and sleep deeply at night.
Four cells in the human retina capture light and form the visual
system. One type, rod cells, regulates night vision. The other
three types, called cone cells, control color vision. It's known that
exposure to light at night can disrupt the body's production of melatonin,
which is produced by the pineal gland in the brain and plays a vital role in
resetting the body's daily biological clock.
Dr. Brainard and his group showed that the combined three-cone system
didn't control the biological effects of light, at least not for melatonin
regulation. But subsequent work led to the surprising discovery that a
novel receptor was responsible for the effect.
The study looked at the effects of nine different wavelengths of light,
from indigo to orange, on 72 healthy volunteers. Subjects were brought into the laboratory at midnight, when
melatonin is highest. The subjects' pupils were dilated and then they
were blindfolded for two hours. Blood samples were drawn. Next,
each person was exposed to a specific dose of photons of one light for 90
minutes, and then another blood sample was drawn. Wavelengths of
blue light had the highest potency in causing changes in melatonin levels,
This new research indicates that there is an as yet unidentified
photopigment; most sensitive at theses wavelengths of blue light that
controls theses neurological reactions to light. As another researcher
notes, this 'provides the first direct evidence of a non-rod, non-cone
photoreceptive system in humans' - one that is activated by blue light
between 420-480 nm. 2
We are pleased to announce that this research has been incorporated into
the BlueStarTM Light Boxes. The 10 000 lux, BlueStarTM double tubes
have one side that's bright blue (446-477 nm) and one side that's bright
white 85 CRI, 5000K. Clinical use shows that the BlueStarTM Light
raises serotonin in 15-30 minutes, instead of the 1-2 hours necessary with
bright hi lux light
Brainard G, Hanifin J, Gresson J, et al (2001)
Action Spectrum for Melatonin Regulation in Humans: Evidence for a
Novel Circadian Photoreceptor. Neurosci (16): 6405-6412
2 Thapan K, Arendt J, Skene DJ (2001) An action spectrum for
melatonin suppression: evidence for a novel non-rod, non-cone
photoreceptor system in humans. J Physiol 535 (pt 1): 261-7
3 Wright HR, Lack LC (2001) Effect of light wavelength on
suppression and phase delay of the melatonin rhythm. Chronobiol Int
4 Max, M (2001) Molecular Basis of Phototransduction and
Circadian Rhythmicity, notes on current research, Dept. of
Physiology and Biophysics of Mount Sinai School
NIACINAMIDE (Nerve protectant and anti-inflammatory)
Immunol. 2003 Jan;131(1):48-52.
is a potent inhibitor of proinflammatory cytokines.
Ungerstedt JS, Blomback M, Soderstrom T.
Coagulation Research, Department of Surgical Sciences, Karolinska
Institutet, Stockholm, Sweden.
The present study investigates the modulating effects of nicotinamide on
the cytokine response to endotoxin. In an in vitro model of endotoxaemia,
human whole blood was stimulated for two hours with endotoxin at 1 ng/ml,
achieving high levels of the proinflammatory cytokines IL-1 beta, IL-6,
IL-8 and TNF alpha. When coincubating whole blood, endotoxin and the
vitamin B3 derivative nicotinamide, all four cytokines measured were
inhibited in a dose dependent manner. Inhibition was observed already at a
nicotinamide concentration of 2 mmol/l. At a concentration of 40 mmol/l,
the IL-1 beta, IL-6 and TNF alpha responses were reduced by more than 95%
and the IL-8 levels reduced by 85%. Endotoxin stimulation activates
poly(ADP-ribose)polymerase (PARP), a nuclear DNA repair enzyme. It has been
hypothesized that the anti-inflammatory properties of nicotinamide are due
to PARP inhibition. In the present study, the endotoxin induced PARP
activation was dose dependently decreased with 4-40 mmol/l nicotinamide or
4-100 micro mol/l 6(5H) phenanthridinone, a specific PARP inhibitor. 6(5H)phenanthridinone
however, failed to inhibit the proinflammatory cytokines. Thus, the
mechanism behind the cytokine inhibition in our model seems not to be due
to PARP inhibition. In conclusion, the present study could not only confirm
previous reports of a down-regulatory effect on TNFalpha, but demonstrates that nicotinamide is a potent modulator
of several proinflammatory cytokines. These findings demonstrate that
nicotinamide has a potent immunomodulatory effect in vitro, and may have
great potential for treatment of human inflammatory disease.
PMID: 12519385 [PubMed - indexed for MEDLINE]
Sci. 2003 May;24(5):228-32.
ｷ Nicotinamide: necessary
nutrient emerges as a novel cytoprotectant for the brain.
Maiese K, Chong ZZ.
Division of Cellular and Molecular Cerebral Ischemia, Wayne
School of Medicine
Detroit, St Antoine, MI 48201, USA. email@example.com
Although usually identified as an essential cellular nutrient for cellular
growth and maintenance, nicotinamide is under development as a novel
cytoprotectant for acute and chronic neurodegenerative disorders. Here, we
outline support for the premise that nicotinamide both prevents and
reverses neuronal and vascular cell injury. Nicotinamide fosters DNA
integrity and maintains phosphatidylserine membrane asymmetry to prevent
cellular inflammation, cellular phagocytosis and vascular thrombosis. The
downstream cellular and molecular cascades are considered vital for the
cytoprotection offered by nicotinamide. These pathways encompass the
modulation of Akt, the forkhead transcription factor FKHRL1, mitochondrial
membrane potential, caspase activities and cellular energy metabolism, but
remain independent of intracellular pH and mitogen-activated protein
kinases. As both a therapeutic agent and an
investigational tool, nicotinamide offers new therapeutic strategies for
degenerative disorders of the CNS.
Biochem. 1999 Mar;193(1-2):119-25.
discovered anti-inflammatory properties of the benzamides and
Pero RW, Axelsson B, Siemann D, Chaplin D, Dougherty G.
Department of Cell and Molecular Biology, University of Lund, Sweden.
Our laboratory has concentrated on the possible regulation the benzamides
and nicotinamides may have on the processes of DNA repair and apoptosis.
Recent reports have suggested that both apoptosis and inflammation are
regulated by the transcription factor NF-kappaB. We have initiated studies
regarding the hypothesis that the benzamides and nicotinamides could
inhibit the production of tumor necrosis factor alpha (TNFalpha) and the
inflammatory response as well as induce apoptosis via inhibition of
NF-kappaB. Our data have shown that nicotinamide and two N-substituted
benzamides, metoclopramide (MCA) and 3-chloroprocainamide (3-CPA), gave
dose dependent inhibition of lipopolysacharide induced TNFalpha in the
mouse within the dose range of 10-500 mg/kg. Moreover, lung edema was
prevented in the rat by 3 x 50 mg/kg doses of 3-CPA or MCA, and 100-200
microM doses of MCA could also inhibit NF-kappaB in Hela cells. Taken together these data strongly support the notion
that benzamides and nicotinamides have potent anti-inflammatory and
antitumor properties, because their primary mechanism of action is
regulated by inhibition at the gene transcription level of NF-kappaB, which
in turn inhibits TNFalpha and induces apoptosis.
PMID: 10331648 [PubMed - indexed for MEDLINE]
Velvet Deer Antler for Remyelination
Deer Antler is rich
in Neurotrophin-3 and IGF, which is a player in nerve remyelination.
Brain Res. 2003
specifically increases mature oligodendrocyte population and enhances
remyelination after chemical demyelination of adult rat CNS.
Jean I, Lavialle C, Barthelaix-Pouplard A, Fressinaud C.
Cell Biology Laboratory, UPRES EA 3143, University
Hospital, 4 rue Larrey, F 49033
Angers cedex 01, France.
In human central nervous system (CNS) demyelinating diseases, spontaneous
remyelination is often incomplete. Therefore, we have tested whether
neutrotrophin-3 (NT-3) accelerates CNS myelin repair after a
chemically-induced demyelination. One group of adult rats was injected in the
corpus callosum (CC) with 1 microl of 1% lysophosphatidylcholine (LPC) and 1
microl of NT-3 (1 microg/microl), and 15 days after injury (D15)
remyelination was compared to control rats (receiving 1 microl of LPC+1
microl of vehicle buffer of NT-3). The demyelinated volume decreased by 56%
in NT-3-treated rats at D15, and immunohistochemistry showed an increase in
mature MBP(+) oligodendrocytes (OL) (+66%) in treated animals (whereas less
mature (CNP(+)) OL were unchanged). Since less than 3% axons degenerate in
this model, and as astrocytic gliosis was not modified, these data suggest that
NT-3 acts directly on cells of the OL lineage to enhance remyelination in
Mol Cell Neurosci.
Neurotrophin-3-mediated regeneration and recovery of
proprioception following dorsal rhizotomy.
Ramer MS, Bishop T, Dockery P, Mobarak MS, O'Leary D, Fraher JP, Priestley
JV, McMahon SB.
CORD (Collaboration on Repair Discoveries), The University of British
Columbia, Biosciences Building, 6270 University Boulevard, Vancouver, British
Columbia V6T 1Z4, Canada.
Injured dorsal root axons fail to regenerate into the adult spinal cord,
leading to permanent sensory loss. We investigated the ability of intrathecal
neurotrophin-3 (NT3) to promote axonal regeneration across the dorsal root
entry zone (DREZ) and functional recovery in adult rats. Quantitative
electron microscopy showed robust penetration of CNS tissue by regenerating
sensory axons treated with NT3 at 1 and 2 weeks postrhizotomy. Light and
electron microscopical anterograde tracing experiments showed that these
axons reentered appropriate and ectopic laminae of the dorsal horn, where
they formed vesicle-filled synaptic buttons. Cord dorsum potential recordings
confirmed that these were functional. In behavioral studies, NT3-treated (but
not untreated or vehicle-treated) rats regained proprioception. Recovery
depended on NT3-mediated sensory regeneration: preventing regeneration by
root excision prevented recovery. NT3 treatment allows sensory axons to
overcome inhibition present at the DREZ and may thus serve to promote
functional recovery following dorsal root avulsions in humans. (C)2002
Elsevier Science (USA).
PMID: 11860276 [PubMed - indexed for MEDLINE]
In studies, Vitamin D has been found
helpful against autoimmunity
for the down-regulation of Th1 and up-regulation of Th2 cells. It has also been
shown to regulate the neurotrophins NGF (Nerve Growth Factor), NT-3
(NeuroTrophin 3) and NT-4. In addition, D3 has also been found to
promote differentiation and cell death in neuroblastoma (brain tumour) cell
lines as well as cancers in general making it a possible weapon against
J Mol Endocrinol.
_Expression of neurotrophin-3 in the growing velvet
antler of the red deer Cervus elaphus.
Garcia RL, Sadighi M, Francis SM, Suttie JM, Fleming JS.
Department of Physiology and Centre for Gene Research, Otago School of
Medical Sciences, Dunedin, New Zealand.
Antlers are organs of bone which regenerate each year from the heads of male
deer. In addition to bone, support tissues such as nerves also regenerate.
Nerves must grow at up to 1 cm/day. The control of this rapid growth of
nerves is unknown. We examined the relative _expression of neurotrophin-3
(NT-3) mRNA in the different tissues of the growing antler tip and along the
epidermal/dermal layer of the antler shaft of the red deer Cervus elaphus, using
semi-quantitative reverse transcription-polymerase chain reaction.
_Expression in the tip was found to be highest in the epidermal/dermal layer
and lowest in the cartilaginous layer in all developmental stages examined.
These data correlate well with the density and pattern of innervation of
these tissues. Along the epidermal/dermal layer of the antler shaft,
_expression was highest in the segments subjacent to the tip and lowest near
the base, arguing for differences in the temporal _expression of NT-3 in
these segments. The _expression of NT-3 in cells isolated from the different
layers of 60-day antlers did not mirror that observed when whole tissues were
used and may suggest regional specificity of NT-3 _expression within antler
PMID: 9343309 [PubMed - indexed for MEDLINE]
J Exp Zool. 1998
Detection of growth factors and proto-oncogene mRNA
in the growing tip of red deer (Cervus elaphus) antler using reverse-transcriptase
polymerase chain reaction (RT-PCR).
Francis SM, Suttie JM.
AgResearch, Invermay Agricultural Centre, Mosgiel, New Zealand.
Deer antler is a unique mammalian organ that has an annual cycle of
regeneration. The antler grows very rapidly from the tip at up to 1 cm/day in
red deer for
a 90- to 120-day period. It is hypothesised that locally produced growth
factors are required to control and stimulate this growth. The tip of the
growing antler from animals whose antlers had been growing for 30, 60, or 90
days was dissected into four zones: epidermis/dermis, reserve mesenchyme,
precartilaginous, and cartilaginous. Total RNA was extracted, and the
presence of various growth factors and proto-oncogenes was detected using
RT-PCR, IGF-I, IGF-II, TGF beta 1, TGF beta 2, c-fos, c-myc, and
beta-actin were all present as single bands of the expected molecular weight
in the four zones of the antler at each stage of growth. There were higher
levels of IGF-I, TGF beta 2, and c-myc relative to beta-actin in the
epidermis/dermis layer than in the other three zones. There were no
differences in the _expression of any of the genes between the three stages
of growth. The presence of TGF beta 3 cannot be confirmed since multiple
bands were seen in all antler tissues. A single band of the expected size for
TGF alpha was seen only in the epidermal/dermal layer of the antler, with
multiple bands of different molecular weight being detected in the other
zones of the antler. This work has demonstrated the presence of multiple
growth factors in the growing deer antler and supports the hypothesis that
paracrine/autocrine stimulation is important for regulating antler growth.
Gene Therapy for ALS Mice and for Patients
Information for Patients: http://www.hopkinsmedicine.org/press/2003/August/030807B.htm
It's not a cure, but a novel form of
gene therapy has delayed symptoms and almost doubled life expectancy in mice
with the equivalent of Lou Gehrig's disease, a team from the Salk Institute
and Johns Hopkins reports in the Aug. 8 issue of Science.
In experiments with mice destined to
develop the condition, injection of the gene for insulin-like growth factor-1
(IGF-1) into muscles protected nerve cells, extended survival and improved
strength, say the scientists, who are planning a clinical trial they hope to
be able to begin in the next year.
The most beneficial treatment ever
seen in the mice, it is also the first to extend animals' survival when given
after symptoms develop, the researchers say. In the experimental mice and in
people with the disease, known as amyotrophic lateral sclerosis or ALS,
nerves that control muscles gradually die, leading to paralysis and death.
"ALS is a terrible disease and
patients have few treatment options today. We're very excited about
this," says Jeffrey Rothstein, M.D., Ph.D., professor of neurology and
neuroscience and director of the Packard
Center for ALS Research
at Johns Hopkins. "Even in mice, progression of the disease is so rapid
that we only test possible treatments before the mice get sick. It is amazing
that this gene therapy can slow progression even after symptoms
Gene therapies use a virus to deliver
specific genetic instructions to cells and usually have to be delivered
directly to where the gene is needed. But instead of injecting this
"adeno-associated" virus into specific nerves in the brain and
spinal cord -- a feat that is likely impossible -- researchers at the Salk
discovered and took advantage of the virus's ability to migrate from muscle
into the nerves that control them. The nerve cells then made the IGF-1
"IGF-1 protein has been used in
clinical trials, but with marginal results," said Fred H. Gage, Ph.D.,
professor of genetics at the Salk Institute. "The biggest challenge has
been to deliver the protein across the blood-brain barrier into the central
Studying a fluorescent version of the
adeno-associated virus, Salk research fellow Brian Kaspar discovered that it
could travel from muscles into nerves. Once in the nerves' nuclei, the cells'
machinery pumped out the glowing protein.
The virus's ability to migrate (known
as "retrograde delivery") into nerves from muscle gets the
therapeutic IGF-1 protein where it appears to be needed most -- the brain and
spinal cord. The researchers showed that when IGF-1 is only produced in
muscle, the benefit is minimal.
Key to the work is a mouse model of
ALS, developed in part at Johns Hopkins. Without any treatment, these mice,
engineered to make extra superoxide dismutase-1 (SOD-1), develop the first
symptoms of weakness at 90 days of age and succumb to the paralysis within
the next 45 days.
Injection of the IGF-1 gene therapy
into both quadriceps (upper hindlimb) muscles and into muscles between the
ribs that help control breathing maintained strength and lengthened survival.
Mice that received IGF-1 gene therapy
at 60 days of age developed symptoms 31 days later than untreated mice (i.e.,
at 121 days) and lived, on average, 40 days longer. The treated mouse that
survived the longest lived 265 days, while the longest-lived control mouse
lived just 140 days. Mice that received injections of IGF-1 gene therapy at
90 days of age lived an average of 22 days longer than their untreated
In addition to planning a clinical
trial, the researchers will also continue to investigate how IGF-1 protects
nerves to improve understanding of the disease and increase the therapeutic
potential of IGF-1.
About 30,000 people in the United States
have ALS, and about 5,000 new cases are diagnosed each year. Most will die
within five years of their diagnosis. While excessive SOD-1 in mice simulates
the effects of the human disease, the cause of ALS in people is not known.
The Johns Hopkins researchers were
funded by Project ALS. The Salk researchers were funded by Project ALS,
Christopher Reeve Foundation, the National Institute on Aging and the
National Institute of Neurological Diseases and Stroke.
Authors on the paper are Kaspar, Gage
and Nushin Sherkat of the Salk Institute for Biological Studies, and
Rothstein and Jeronia Llado of The Johns Hopkins University School of
***Patients interested in ALS
treatment at Johns Hopkins
should call 410-955-8511. A clinical trial using IGF-1 gene therapy at Johns Hopkins is being
planned, but is still about a year from starting. A list of prospective
participants will not be maintained.
On the Web:
The Robert Packard
Center for ALS Research
at Johns Hopkins:
Vitamin B1 (Thiamine) for Remyelination
Dr. Stern, at Columbia University,
was using intraspinal injections of thiamine hydrochloride for MS back in the
1940s or so. Patients so treated did not appear to progress. Subsequent
research indicates that thiamine helps promote remyelination (See
Multiple Sclerosis and other demyelinating diseases
To the Editor:
Multiple sclerosis has been defined as
a chronic progressive disease of the central nervous system, or rather a
series of syndromes based on several as-yet-undetermined causative factors.・The etiologic factor or factors are
unknown, but Harrison・has
emphasized its relationship to other demyelinating processes. The
pathological change underlying multiple sclerosis is presumed to be
demyelination in scattered areas of the brain and spinal cord in plaques of
varying size. There is associated edema of the axons and, with progression,
degeneration and loss of function. Vitamins B1 and B12
axe both essential components of myelin. Because demyelination of long nerve
axons in the spinal cord is characteristic of severe vitamin B deficiency and
because this vitamin arrests demyelination in combined system disease, it has
been used in the treatment of multiple sclerosis with varying results.・SUP>4~
On the theory that demyelination
results from the lack of vitamin B1 and some factor or factors in liver
extract, a therapeutic trial was initiated by the undersigned in 1943. The
purpose of this letter is to report the results of that trial.
Materials and methods: Patients were selected on the basis of a history of neurologic deficits
suggestive of multiple sclerosis which had been confirmed by neurologic
investigation and, in most patients, by a second opinion. The presence of
paralysis was felt to be a contraindication to this type of therapy. Fourteen
patients were followed up for periods varying from several months to 29 years
Routine therapy consisted of
intravenous thiamine hydrochloride, 150 mg., plus intramuscular injections of
liver extract (Therapy was begun with Lederle痴 liver extract, but production ceased in the spring of 1972. Connaught
Laboratory liver, extract was used for a period of nine months. Lilly痴 liver extract is now used.), 20 mcg
(1 ml.), every seven to 10 days for a series of 10 treatments. The patient
was then re-evaluated neurologically. Further treatment was recommended
depending on the status of the neurologic deficit and the response.
Results and conclusions: The results in the treated patients are summarized in Table I. No patient
had progression of the disease while on treatment. When symptoms recurred on
cessation of treatment, they were controlled by resumption of therapy.
When vitamins B1 and B12 were
given simultaneously to one patient (case 1) on two occasions (owing to
sensitization to liver extract) the patient experienced progression of her
deficit. When liver extract and vitamin B1 therapy was resumed
(following desensitization) she improved.
A trial of thiamine hydrochloride, 100
mg. daily by mouth, with regular liver extract therapy (case 4) led to return
of symptoms. When routine therapy was again resumed all symptoms cleared. It
would appear that some persons may not absorb vitamin B1 through
the gastrointestinal tract.
Patients treated in the early stages
of the disease responded well and within a time span appropriate to the
presumed underlying pathology of demyelination. Patients in whom the disease
was more advanced responded more slowly. Early treatment of the disease or
its recurrent symptoms seemed to be more important than the age of the
patient. For example, one patient (case 1) now aged 55, still returns
for treatment when she considers it necessary because of a lowered sense of
well-being, increased fatigue, and a tingling sensation in her hands and
feet. Thirty-three years after the onset of her illness and after bed
confinement for two years, she is active, does her housework, walks out alone
without a cane and enjoys an active social life.
The exact stage of pathological change
in any patient cannot be determined.1 It is logical to assume,
however, that the axis cylinders had not been destroyed in any of the
patients in this study, even in case 3, a 59-year-old man who refused to
accept active therapy until his disease, after many years, had induced almost
total incapacity, including poor writing ability and spastic and ataxic gait
with dragging of the left foot. His clinical improvement continues and we
must assume that remyelination is taking place. At present, this man uses a
cane only on the street, can step up with either foot and even uses a ladder.
His manual dexterity is good and he writes well.
My experience, like that of Evers,・ suggests that early treatment is
important in producing symptomatic relief and a state of well being. In case
2, the patient was treated within six months of the onset of severe symptoms
at age 43, made a rapid recovery and gave birth to a normal child two years
later. On several occasions, because of irregular therapy, her symptoms
recurred, but when treatment was resumed she improved rapidly. Now, at the
age of 69, she is active and able to do her housework. In case 4, treatment
was instituted within three years of the onset of the disease. The patient
cooperated completely and therapy was continued without interruption. After
nine months he stated that he felt perfectly well.
The effects of cessation and
resumption of therapy are most clearly demonstrated in case 11. Following
initial treatment from 1962 to 1964, her condition was improved and treatment
was discontinued. In 1967, because of recurrence of symptoms, therapy was
resumed on an irregular basis with subsequent improvement. In February 1971 the
patient returned with symptoms of fatigue, inability to work, loss of balance
and staggering gait. She was not able to return for therapy until March 1972,
at which time her neurologic condition had worsened. She had visual and
auditory difficulty, scanning speech and poor writing ability, unsteady gait
and poor sense of balance. Routine therapy was recommenced and by June 20 of
the same year she was able to return to work as a typist and stated that she
felt perfectly well.
The protracted and capricious natural history of multiple sclerosis
precludes dogmatic statements regarding the effect of a new therapeutic
modality. Furthermore, the exact diagnostic criteria of multiple sclerosis
are uncertain, leading to a frequent diagnosis by exclusion appropriate to
the uncertainty regarding etiology and pathogenesis. However, with regard to
the therapy presented here, patients with two other types of demyelinating
diseases have been successfully treated. One of these, a patient with
advanced bulbar palsy, is now almost completely asymptomatic. The other, a
patient with subacute combined sclerosis who was totally incapacitated,
became neurologically entirely negative. My experience suggests that some
factor or factors in liver extract, associated with vitamin B1, can
induce remyelination in patients suffering from multiple sclerosis and
probably in other cases of demyelinating diseases. It is suggested that this
clinical finding should now be subjected to detailed laboratory studies in
order to enlarge its use or to circumscribe its limitations.
H.T. R. Mount, M.B., M.S.,F.R.C.S.[C], F.A.C.S.
203 - 340 McLeod St.,
Ottawa, Ont. K2P 1A4
1. WECHSLER IS: Clinical neurology, ninth ed. Philadelphia, WB Saunders, 1963
2. HAIws0N TR: Principles of Internal Medicine, sixth ed, vol 2. Toronto, McGraw-Hill,
1970, pp 1080-2016
3. LEHRER GM: Etiology, diagnosis and treatment of multiple sclerosis. Mod
Treat 7: 1970
4. Cures for multiple sclerosis. Br MedJ I: 59, 1970
5. NORMAN CS: Vitamin B,, plasma clearance in multiple sclerosis. Jr
I Med Sd 6: 333, 1966
6. MERRITT, HN: Textbook of Neurology, fourth ed. Philadelphia, Lea and Febiger, 1967, pp
7. NAMEROW NS, THOMPSON LR:Plaques, symptoms, and the
remitting course of multiple sclerosis. Neurology (Minneap) 19: 765,
8. SIMPSON CA, NEWELL DJ, MILLER H: The treatment of
multiple sclerosis with massive doses of hydroxycobalamin. Neurology 15:
9. EVERS J: Dietetic therapy of multiple sclerosis Med Welt 20:
Extracted from C.M.A. JOURNAL/JUNE 2, 1973/VOL. 108
Mushroom for Remyelination
influence of Hericium erinaceus extract on myelination process in vitro.
Kolotushkina EV, Moldavan MG, Voronin KY, Skibo GG.
A.A. Bogomoletz Institute of Physiology, National Academy
of Sciences, Kiev.
Myelin sheaths, wrapping axons, perform the following important functions:
support, protection, feeding and isolation. Injury of myelin compact
structure leads to an impairment and severe illness of the nerve system.
Exact mechanisms underlying the myelination process and myelin sheaths damage
have not established yet. Therefore search for substances, which provide
regulatory and protective effects on the normal myelination as well as
stimulating action on the remyelination after myelin damage, is of special
interest. Recently it was shown that extract from mushroom Hericium
erinaceus had activating action on the nerve tissue. So the aim of the
present work was to study an influence of an extract from H. erinaceus on the
cerebellar cells and the process of myelination in vitro. Obtained data
revealed the normal growth of the nerve and glial cells with extract at
cultivating. No pathologic or toxic action of the extract has been found.
The cell ultrastructure was intact and similar to that observed in vivo. The
process of myelination in the presence of the extract began earlier as
compared to controls and was characterised by a higher rate. Thus, extract of
H. erinaceus promoted normal development of cultivated cerebellar cells and
demonstrated a regulatory effect on the process of myelin genesis process in
- 500 mgs to 1 gram
between meals should prove beneficial in MS and ALS patients
J Neurosci Res. 2001 Nov 15;66(4):612-9.
taurine in regulation of intracellular calcium level and neuroprotective
function in cultured neurons.
Chen WQ, Jin H, Nguyen M, Carr J, Lee YJ, Hsu CC, Faiman MD, Schloss JV,
Department of Molecular Biosciences, University
of Kansas, Lawrence, Kansas 66045, USA.
Glutamate-induced excitotoxicity has been implicated as an important
mechanism underlying a variety of brain injuries and neurodegenerative
diseases. Previously we have shown that taurine has protective effects
against glutamate-induced neuronal injury in cultured neurons. Here we
propose that the primary underlying mechanism of the neuroprotective
function of taurine is due to its action in preventing or reducing
glutamate-induced elevation of intracellular free calcium, [Ca(2+)](i).
This hypothesis is supported by the following findings. First, taurine
transport inhibitors, e.g., guanidinoethyl sulfonate and beta-alanine, have
no effect on taurine's neuroprotective function, suggesting that taurine
protects against glutamate-induced neuronal damage through its action on
the extracellular membranes. Second, glutamate-induced elevation of
[Ca(2+)](i) is reduced to the basal level upon addition of taurine. Third,
pretreatment of cultured neurons with taurine prevents or greatly
suppresses the elevation of [Ca(2+)](i) induced by glutamate. Furthermore,
taurine was found to inhibit the influx but not the efflux of (45)Ca(2+) in
cultured neurons. Taurine has little effect on the binding of
[(3)H]glutamate to the agonist binding site and of [(3)H]MDL 105,519 to the
glycine binding site of the N-methyl-D-aspartic acid receptors, suggesting
that taurine inhibits (45)Ca(2+) influx through other mechanisms, including
its inhibitory effect on the reverse mode of the Na(+)/Ca(2+) exchangers
(Wu et al.  In: Taurine 4: taurine and excitable tissues. New York: Kluwer
Academic/Plenum Publishers. p 35-44) rather than serving as an antagonist
to the N-methyl-D-aspartic acid receptors. Copyright 2001 Wiley-Liss, Inc.
Dietary Exorphins ・
Morphine-Like compounds that fuel inflammation
MS and ALS patients would be well advised to
eliminate all grains, cereals and bovine milk in order to stop exorphin
production in their bodies!
Ann N Y Acad Sci. 2002
ｷ Role of nitric oxide in
Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS.
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National
Institute of Environmental Health Sciences/National Institutes of Health,
Research Triangle Park, North Carolina 27710, USA. firstname.lastname@example.org
Increasing evidence has suggested that inflammation in the brain is closely
associated with the pathogenesis of several degenerative neurologic
disorders, including Parkinson's disease, Alzheimer's diseases, multiple
sclerosis, amyotrophic lateral sclerosis, and AIDS dementia. The hallmark of
brain inflammation is the activation of glial cells, especially that of
microglia that produce a variety of proinflammatory and neurotoxic factors,
including cytokines, fatty acid metabolites, free radicals--such as nitric
oxide (NO) and superoxide. Excessive production of NO, as a consequence of
nitric oxide synthase induction in activated glia, has been attributed to
participate in neurodegeneration. Using primary mixed neuron-glia cultures
and glia-enriched cultures prepared from embryonic rodent brain tissues, we
have systemically studied the relationship between the production of NO and
neurodegeneration in response to stimulation by the inflammagen
lipopolysaccharide. This review summarizes our recent findings on the
kinetics of NO generation, the relative contribution of microglia and
astrocytes to NO accumulation, the relationship between NO production and
neurodegeneration, and points of intervention along the pathways associated
with NO generation to achieve neuroprotection. We
also describe our results relating to the effect of several opioid-related
agents on microglial activation and neuroprotection. Among these agents, the
opioid receptor antagonist naloxone, especially its non-opioid enantiomer
(+)-naloxone, promises to be of potential therapeutic value for the treatment
of inflammation-related diseases.
J Neurosci. 2003
Therapeutic action of cannabinoids in a murine
model of multiple sclerosis.
Arevalo-Martin A, Vela JM, Molina-Holgado E, Borrell J, Guaza C.
Neuroimmunology Group, Neural Plasticity Department, Cajal Institute,
Consejo Superior de Investigaciones Cientificas, 28002 Madrid, Spain.
Theiler's virus infection of the CNS induces an immune-mediated
demyelinating disease in susceptible mouse strains and serves as a relevant
infection model for human multiple sclerosis (MS). Cannabinoids may act as
immunosuppressive compounds that have shown therapeutic potential in chronic
inflammatory disorders. Using the Theiler's murine encephalomyelitis virus
model, we report here that treatment with the synthetic cannabinoids WIN
55,212-2, ACEA, and JWH-015 during established disease significantly
improved the neurological deficits in a long-lasting way. At a histological
level, cannabinoids reduced microglial activation, abrogated major
histocompatibility complex class II antigen _expression, and decreased the
number of CD4+ infiltrating T cells in the spinal cord. Both recovery of motor
function and diminution of inflammation paralleled extensive remyelination.
Overall, the data presented may have potential therapeutic implications in
demyelinating pathologies such as MS; in particular, the possible
involvement of cannabinoid receptor CB2 would enable nonpsychoactive
therapy suitable for long-term use.
AIDS Treat News.
1996 Oct 18;(No 257):3-4.
AIDS: Three substances in chocolate and cocoa powder may mimic cannabinoid
by activating receptors or increasing anandamide levels. Anandamide is a
lipid that binds to cannabinoid receptors and mimics the psychoactive
effects of the drug. Chocolate is widely believed to enhance the effect of
marijuana. A practical implication of this finding is that the amount of
marijuana needed for medicinal purposes may be decreased by using it with
chocolate, reducing both the risks and cost associated with marijuana.
Nature. 1996 Aug
Nature. 1998 Dec 17;396(6712):636-7.
cannabinoids in chocolate.
di Tomaso E, Beltramo M, Piomelli D.
Lipoic Acid as a Possible Treatment for Multiple Sclerosis
Scientists believe that oxidative injury may be
associated with multiple sclerosis (MS). Mice with experimental autoimmune
encephalomyelitis (EAE), an experimental model of MS, were given Alpha Lipoic
Acid to treat. The mice showed a reduction of encephalomyelitis symptoms of
between 23% - 100%, with minimal inflammation, demyelination and axonal loss
in the spinal cords. The scientists conducting the research concluded, "ALA is highly
effective at suppressing and treating EAE and does so by inhibiting T cell
trafficking into the spinal cord, perhaps by acting as a matrix
metalloproteinase inhibitor." While emphasizing that more research is
required, researchers believe that ALA
may have potential as a treatment for MS.
Also, high iron
levels in the gray matter (brain) of MS patients has been linked to both
cognitive and physical deficits (See below)! Interestingly, alpha lipoic acid
appears to help decrease iron in tissues (The pharmaceutical desferrioxamine
also does this quite effectively). Abstracts follow the Science Daily
Matter Damage In The Brain Of MS Patients Linked To Cognitive, Physical
BUFFALO, N.Y. -- The mental impairment and problems with walking
experienced by patients with multiple sclerosis (MS) are linked to damage in
the brain's gray matter, with MRI findings suggesting the damage is due to
toxic deposits of iron, researchers from the University at Buffalo have shown for the first time.
Previous breakthrough work by the team had linked deep gray matter iron
deposits to the disease course of MS, brain atrophy and overall disability,
but not to cognition or ambulation. Results of these latest studies were
presented today (Oct. 21, 2003) at the annual meeting of the American
Neurological Association in San
The researchers, affiliated with the Buffalo Neuroimaging Analysis Center
(BNAC) and Jacobs Neurological Institute, use specialized, computer-assisted
magnetic resonance imaging (MRI) technology to focus on hypointensity, or
unnatural darkness, of gray matter structures as seen on so-called
T2-weighted images. This condition is referred to as T2 hypointensity. Using
this approach, they were able to show that structures in the brain's deep
gray matter of MS patients contained T2 hypointensity compared with normal
individuals, suggesting higher-than-normal levels of iron deposits, and
confirmed the relationship of T2 hypointensity to MS symptoms.
"Traditionally, we thought MS was strictly a 'white matter disease,'
involving the brain's neural pathways that allow various gray-matter structures
to communicate with each other," said Rohit Bakshi, M.D., UB associate
professor of neurology, first author on the new studies and founding director
of the BNAC. "Through our computerized imaging analysis capabilities, we
were able to visualize gray matter structures deep in the brain of MS
patients and found some to be atrophied.
"We also found MRI evidence of abnormally high levels of iron,"
he said. "Moreover, these changes weren't associated with the amount of
white-matter damage, so this was all new information. If we're going to treat
this disease, we have to know where the damage is."
The finding concerning gray matter atrophy resulted from the researchers'
work with a brain structure called the caudate nucleus, which is an important
nerve center for controlling movement and cognitive processing. Other
laboratories have studied the role of the caudate nucleus in Alzheimer's
disease and Huntington's disease, but the BNAC is the only center studying it
in MS patients using state-of-the-art MRI techniques. The current studies
take the BNAC's previous research to the next level, in an effort to
determine the role of excess iron in specific MS disabilities. Bakshi and
colleagues tested walking ability and cognitive impairment respectively in
two groups of MS patients that underwent the specialized MRI brain scans to
assess T2 hypointensity of the gray matter structures thought to be involved
in these conditions.
The ambulatory study involved 41 MS patients who completed a timed
25-foot walk, a standard measure of physical dysfunction. These times were
compared with T2 hypointensity in the gray matter, as well as brain atrophy
and additional anatomical brain changes known to occur in MS. Results showed
that T2 hypointensity was the only brain change directly associated with
impaired walking ability, and the strongest association with walking ability
pointed to the brain structure known as the dentate nucleus. This structure
exists deep in the cerebellum, the brain region responsible for coordination
and smooth movement of the limbs.
The study of cognitive impairment involved 28 MS patients who took tests
measuring learning, speed of information processing and working memory. Test
results were compiled into an attention/memory composite, which was compared
with the same measures of brain change used in the ambulation assessment. T2
hypointensity in the brain's deep gray matter structures was the only measure
that predicted cognitive impairment in these patients, results showed.
"We suspect that MS patients have defective blood-brain barriers,
the cell layer that prevents potentially toxic substances from entering the
brain," Bakshi said. "Excessive iron entering the brain may damage
the deep gray matter structures through generation of free radicals and lipid
peroxidation, as well as inflammation, all of which would destroy neurons. We
have tissue samples from two autopsied brains showing high iron levels in
these gray matter structures in patients with MS compared to controls."
Bakshi said the other possibility is that high levels of iron are a
result of the neurodegenerative process that occurs in MS. "When brain
cells are destroyed, in aging for example, iron levels increase in the brain.
High levels of iron also are seen in Alzheimer's and Parkinson-related diseases.
There is still a debate about cause-effect of iron in all of these
"We do think, however, that hypointensity in the deep gray matter is
a strong predictor of disability, progression of the disease and subsequent
brain atrophy in MS," he said. "If future longitudinal studies
support these findings, it may be possible to design a new treatment to
prevent iron build-up, which could prove beneficial to MS patients. However,
we must have further studies to draw definitive conclusions," stated
Additional researchers on the studies were Christopher Tjoa, a first-year
UB medical student; Ralph Benedict, Ph.D., UB neuropsychologist and associate
professor of neurology; Andrew Fabiano, third-year UB medical student;
Jitendra Sharma, M.D., a graduate student at Roswell Park Cancer Institute;
Robert Bermel, fourth-year UB medical student; Frederick E. Munschauer, M.D.,
professor and chair of the UB Department of Neurology, and Bianca
Weinstock-Guttman, M.D., assistant professor of neurology.
The studies were funded by grants from the National Institutes of Health,
National Science Foundation and the National Multiple Sclerosis Society, and
by an Alpha Omega Alpha medical school research fellowship and an American Academy of Neurology Student Interest
in Neurology Summer Scholarship.
This story has been adapted from a
news release issued by University At Buffalo.
Exp Eye Res. 2003
Alpha lipoic acid changes iron uptake and storage in
lens epithelial cells.
Goralska M, Dackor R, Holley B, McGahan MC.
Department of Molecular Biomedical Sciences, North Carolina State University,
4700 Hillsborough Street, Raleigh, NC 27606, USA.
Alpha lipoic acid (LA) is a cofactor in mitochondrial dehydrogenase
complexes. Previous studies have shown that when administered exogenously LA
has antioxidant properties, which include free radical scavenging, metal
chelation and regeneration of other antioxidants. The cells convert LA into
dihydroplipoic acid (DHLA), which in the presence of iron can act as a
prooxidant. In vitro DHLA reduces Fe(+3) to Fe(+2) and removes iron from
ferritin, increasing the risk of Fe catalyzed free radical formation. In the
present study we examined the in vivo effects of lipoic acid treatment on Fe
metabolism in cultured lens epithelial cells, and found that LA decreases Fe
uptake from transferrin, increases Fe deposition into ferritin and increases
the concentration of this protein. When administered together with ascorbic
acid, lipoic acid changes the characteristic heavy to light chain ratio of
ferritin makeup. The decreased Fe uptake and increased storage diminishes the
size of the cytosolic highly reactive Fe pool (LIP). These changes are
associated with increased cell resistance to H(2)O(2) challenge. Therefore,
LA may reduce the risk of Fe induced oxidative damage and also might be
useful as a treatment of Fe overload. Copyright 2003 Elsevier Science Ltd.
PMID: 12565812 [PubMed - indexed for MEDLINE]
acid and alpha-lipoamide prevent oxidant-induced lysosomal rupture and
Persson HL, Svensson AI, Brunk UT.
Division of Pathology II, Faculty of Health Sciences, Linkoping University, Sweden.
Alpha-lipoic acid (LA) and its corresponding derivative, alpha-lipoamide
(LM), have been described as antioxidants, but the mechanisms of their
putative antioxidant effects remain largely uncharacterised. The vicinal
thiols present in the reduced forms of these compounds suggest that they
might possess metal chelating properties. We have shown previously that cell
death caused by oxidants may be initiated by lysosomal rupture and that this
latter event may involve intralysosomal iron which catalyzes Fenton-type
chemistry and resultant peroxidative damage to lysosomal membranes. Here,
using cultured J774 cells as a model, we show that both LA and LM stabilize
lysosomes against oxidative stress, probably by chelating intralysosomal iron
and, consequently, preventing intralysosomal Fenton reactions. In preventing
oxidant-mediated apoptosis, LM is significantly more effective than LA, as
would be expected from their differing capacities to enter cells and
concentrate within the acidic lysosomal compartment. As previously reported,
the powerful iron-chelator, desferrioxamine (Des) (which also locates within
the lysosomal compartment), also provides protection against oxidant-mediated
cell death. Interestingly, although Des enhances the partial protection
afforded by LA, it confers no additional protection when added with LM.
Therefore, the antioxidant actions of LA and LM may arise from intralysosomal
iron chelation, with LM being more effective in this regard.
PMID: 11778851 [PubMed - indexed for MEDLINE]
Non-toxic NDGA and Acetyl-L-Carnitine
According to numerous published studies,
leukotrienes do play a role in Multiple Sclerosis and ALS. Many of the
natural compounds above do help curtail synthesis
of this class of highly inflammatory substances. However, I do not feel they are as effective as NDGA. Bad news: The NDGA in
most herbs is toxic. Good news:
There is a patented nontoxic form that has been available now for
some years -- Larreastat (TM). Given the role of leukotrienes in MS and
ALS, and the availability of a nontoxic NDGA product, it follows that
people with neurodegenerative/neuroinflammatory disorders and conditions
might want to consider incorporating this in their health support regimen.
(I would also recommend employing acetyl-L-carnitine, as it confers many
health benefits specific to neurological diseases & disorders. Also, N-acetylcysteine (NAC), as this is used in the human body to synthesis
the intracellular antioxidant, glutathone).
Acetyl-L-Carnitine ・Any brand
or a generic is fine. 1 gram twice daily, preferably on an empty stomach.
(NAC). Any brand or a generic is fine. 800 mgs. ・1 gram
twice dail, preferably on an empty stomach.
Acta Neurol Scand.
Leukotrienes in patients with clinically active
Neu IS, Metzger G, Zschocke J, Zelezny R, Mayatepek E.
Department of Neurology, Municipal Hospital, Academic Teaching, Hospital
of Tubingen University, Sindelfingen, Germany. email@example.com
OBJECTIVES: The role of leukotrienes (LTs) in the pathophysiology of multiple
sclerosis (MS) has been controversially discussed in the past. Studies of LTs
in the cerebrospinal fluid (CSF) revealed different results mainly because of
analytical difficulties. MATERIAL AND METHODS: In the present study we used
highly sensitive and specific analytical methods for measuring LTs in the CSF
as well as in urine samples from 20 patients with active MS and 20 control
patients with noninflammatory neurological disorders. RESULTS: LTB4
concentrations in CSF were almost twice as high in MS patients compared with
controls (P < 0.001). CSF concentrations of the cysteinyl-LTs (LTC4, LTD4
and LTE4) as well as urinary LTE4 showed no significant differences compared
with controls (P > 0.05). In addition, there was no significant
association between CSF pleocytosis, clinical severity or time of disease
onset. CONCLUSIONS: The increased concentration of LTB4 in the CSF of MS
patients may indicate a biological importance for this mediator in MS.
Lek. 1997 Apr;2(10):254-5.
B4 and C4 in cerebrospinal of patients with multiple sclerosis]
[Article in Polish]
Rosnowska M, Cendrowski W, Sobczyk W.
Zakladu Biochemii Instytutu Psychiatrii i Neurologii w Warszawie.
Leukotrienes B4 and C4 have been assayed in CSF of 24 patients with the
attacks or slowing-progressing course of multiple sclerosis, and in 23
patients with other noninflammatory diseases. Leukotrienes concentrations
have been assayed with RIA technique with the use of commercially available kits
manufactured by Amersham. Leukotrienes B4 and C4 levels in CSF of patients
with multiple sclerosis have been 91.8 +/- 5.6, and 88.6 +/- 7.5 pg, and have
been significantly higher than those in other neurological disorders (p <
0.01). Mean LTB4 and LTC4 levels have been significantly lower in patients
with atherosclerotic dementia (69, 12.2 and 63, 02.9 pg/ml) or in patients
with headache (72.7 +/- 2.8 and 64.5 +/- 8.2 pg/ml). Higher LTB4 and LTC4
levels in patients with multiple sclerosis is probably due to both increased
penetration through blood-brain barrier and their synthesis in blood-brain
barrier, and cerebral nervous tissue. Further investigations are necessary to
show whether LTB4 and LTC4 levels may indicate a stage of inflammatory
process activity and enable to draw any conclusions on efficacy of
Acta Neurol Scand.
in the cerebrospinal fluid of multiple sclerosis patients.
Neu I, Mallinger J, Wildfeuer A, Mehlber L.
Sindelfingen Municipal Hospital,
The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in
the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51
with other neurological diseases. The LTB4 and LTC4 levels were significantly
elevated in MS compared with the controls. The findings suggest that
lipoxygenase products might play a pathogenetic role in the early,
encephalitogenic phase of MS. The administration of lipoxygenase inhibitors
or leukotriene antagonists might well open new perspectives for the treatment
of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of
patients with active multiple sclerosis: evidence for a protective role of
Calabrese V, Scapagnini G, Ravagna A, Bella R, Butterfield DA, Calvani M,
Pennisi G, Giuffrida Stella AM.
Department of Chemistry, Section of Biochemistry and Molecular Biology.
Faculty of Medicine, University of Catania, Catania,
Recent studies suggest that NO and its reactive derivative peroxynitrite are
implicated in the pathogenesis of multiple sclerosis (MS). Patients dying
with MS demonstrate increased astrocytic inducible nitric oxide synthase
activity, as well as increased levels of iNOS mRNA. Peroxynitrite is a strong
oxidant capable of damaging target tissues, particularly the brain, which is
known to be endowed with poor antioxidant buffering capacity. Inducible nitric
oxide synthase is upregulated in the central nervous system (CNS) of animals
with experimental allergic encephalomyelitis (EAE) and in patients with MS.
We have recently demonstrated in patients with active MS a significant
increase of NOS activity associated with increased nitration of proteins in
the cerebrospinal fluid (CSF). Acetylcarnitine is proposed as a therapeutic
agent for several neurodegenerative disorders. Accordingly, in the present
study, MS patients were treated for 6 months with acetylcarnitine and
compared with untreated MS subjects or with patients noninflammatory
neurological conditions, taken as controls. Western blot analysis showed in
MS patients increased nitrosative stress associated with a significant
decrease of reduced glutathione (GSH). Increased levels of oxidized
glutathione (GSSG) and nitrosothiols were also observed. Interestingly,
treatment of MS patients with acetylcarnitine resulted in decreased CSF
levels of NO reactive metabolites and protein nitration, as well as increased
content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis that
nitrosative stress is a major consequence of NO produced in MS-affected CNS
and implicate a possible important role for acetylcarnitine in protecting
brain against nitrosative stress, which may underlie the pathogenesis of MS.
Curr Med Chem.
thiol concentration modulating inflammatory response: influence on the
regulation of cell functions through cysteine prodrug approach.
Pharma R&D, Zambon Group Spa, Via Lillo del Duca, 10, 20091 Bresso, Milano, Italy.
Oxidative stress is defined as the consequence of overpowering of the immune
system's reaction, which causes increased production of the reactive
oxidative species (ROS) greater than the antioxidant protection. Tissue
injury and oxidation of the circulating molecules may be the consequences.
Moreover, the sulphur-containing amino acids (SAA) fate is perturbed during
stress. The altered biochemical rules during inflammation weaken the
anti-oxidant mechanism, and the extra-supply of SAA under inflammatory
conditions can help to restore homeostasis. In brief, the main biochemical
steps during inflammation are: The production of Cytokines, Acute Phase
Protein, and Glutathione (GSH) pool are strongly modified during
inflammation. * The GSH participates in many important physiological
processes controlling the homeostasis of the cells. * A higher demand of
Cysteine (Cys) supply causes difficulties in maintaining a constant GSH
level. * The role of GSH as a key regulator of thiol redox intracellular
balance is established. This reveals that GSH is essential in regulating the
cell's life cycle and that the reduction of intracellular GSH contributes to
chronic inflammation. The fact that Cys availability is generally a limiting
factor for the GSH synthesis stimulated the development of a
pharmacologically useful Cys pro-drug. The simplest derivative is
N-acetylcysteine (NAC), which appears to be the prototype of all Cys
suppliers. Different approaches are presented here.
2002 Sep 6;329(3):334-8.
Acetyl-L-carnitine shows neuroprotective and
neurotrophic activity in primary culture of rat embryo motoneurons.
Bigini P, Larini S, Pasquali C, Muzio V, Mennini T.
Laboratory for Receptor Pharmacology, Mario Negri Institute for
Pharmacological Research, Via Eritrea,
62, 20157 Milan, Italy. firstname.lastname@example.org
We evaluated the role of acetyl-L-carnitine (ALCAR) in protecting primary
motoneuron cultures exposed to excitotoxic agents or serum-brain derived
neurotrophic factor (BDNF) deprived. To exclude that ALCAR works as a
metabolic source, we compared its effects with those of L-carnitine (L-CAR),
that seems to have no neurotrophic effect. A concentration of 10 mM ALCAR,
but not L-CAR, significantly reduced the toxic effect of 50 microM
N-methyl-D-aspartate (NMDA, % viability: NMDA 45.4+/-2.80, NMDA+ALCAR
90.8+/-11.8; P<0.01) and of 5 microM kainate in cultured motoneurons (%
viability: kainate 40.66+/-10.73; kainate+ALCAR 63.80+/-13.88; P<0.05).
The effect was due to a shift to the right of the dose-response curve for
kainate (EC50 for kainate 5.99+/-1.012 microM; kainate+ALCAR 8.62+/-1.13 microM;
P<0.05). ALCAR, but not L-CAR, significantly protected against BDNF and
serum-deprivation reducing the apoptotic cell death (% viability respect to
control: without BDNF/serum 61.8+/-13.3: without BDNF/serum+ALCAR
111.8+/-13.9; P<0.01). Immunocytochemistry showed an increase in choline
acethyltransferase and tyrosine kinaseB receptors in motoneurons treated with
ALCAR but not with L-CAR. These results suggest that ALCAR treatment improves
the motoneurons activity, acting as a neurotrophic factor.
PMID: 12183043 [PubMed - indexed for MEDLINE]
hormone activates oligodendrocyte precursors and increases a myelin-forming
protein and NGF content in the spinal cord during experimental allergic
Calza L, Fernandez M, Giuliani A, Aloe L, Giardino L.
Department of Veterinary Morphophysiology and Animal Production, University of Bologna,
40064 Ozzano Emilia, Bologna,
Remyelination in the adult central nervous system has been demonstrated in
different experimental models of demyelinating diseases. However, there is no
clear evidence that remyelination occurs in multiple sclerosis, the most
diffuse demyelinating disease. In this article, we explore the possibility of
promoting myelination in experimental allergic encephalomyelitis, a widely
used experimental model of multiple sclerosis, by recruiting progenitors and channeling them into
oligodendroglial lineage through administration of thyroid hormone (T4).
A large number of proliferating cells (BrdUrd uptake and Ki67-IR) and the
_expression of markers for undifferentiated precursors (nestin) increased in
the subventricular zone and spinal cord of experimental allergic
encephalomyelitis animals. T4 administration reduces proliferation and
nestin-immunoreactivity and up-regulates _expression of markers for oligodendrocyte
progenitors [polysialylated-neural cell adhesion molecule (PSA-NCAM), O4,
A2B5] and mature oligodendrocytes (myelin basic protein) in the spinal cord,
olfactory bulb, and subventricular zone.
PMID: 11867745 [PubMed - indexed for MEDLINE]
Complete Paper: http://www.pubmedcentral.gov/picrender.fcgi?artid=122506&blobtype=pdf
Glutamate uptake by oligodendrocytes:
Implications for excitotoxicity in multiple sclerosis.
Pitt D, Nagelmeier
HC, Raine CS.
Department of Neurology, Albert Einstein College
of Medicine, Bronx, NY, USA.
BACKGROUND: Excitotoxic damage is a common pathologic event in a number of
neurologic diseases occurring after accumulation of excess extracellular
glutamate in the CNS and subsequent overstimulation of glutamate receptors.
In gray matter, astrocytes take up synaptically released glutamate and are
thus key cells in maintaining glutamate homeostasis. In white matter,
oligodendrocytes have been shown to express glutamate transporters, but their
role in extracellular glutamate removal is unclear. OBJECTIVE: To investigate
whether cultured human fetal oligodendrocytes functionally express the main
glutamate transporters EAAT-1 and EAAT-2. METHODS: Cultures of fetal human
oligodendrocytes were examined by immunocytochemistry and [3H]glutamate
uptake, and the findings were correlated with glutamate transporter
_expression in normal and multiple sclerosis (MS) CNS tissue. RESULTS: Both
EAAT-1 and EAAT-2 were expressed by human oligodendrocytes in vitro.
Incubation of oligodendrocytes with the proinflammatory cytokine tumor
necrosis factor-alpha (TNFalpha) reduced EAAT-1 _expression and inhibited
glutamate uptake by >75%. Furthermore, in normal human white matter,
oligodendrocytes were found to be the predominant cells to express EAAT-1 and
EAAT-2, both at the mRNA and at the protein level. A small number of
astrocytes in white matter expressed these receptors, more so EAAT-1 than
EAAT-2. In MS white matter, oligodendrocytes lost _expression of EAAT-1 and
EAAT-2 receptors in the lesion vicinity. CONCLUSIONS: Oligodendrocytes appear
to be predominant cells for glutamate clearance in human white matter.
Glutamate receptor _expression and glutamate removal were defective in MS
white matter, possibly mediated by TNFalpha, changes that might underlie high
extracellular glutamate and an increased risk for glutamate excitotoxicity.
PMID: 14581674 [PubMed - indexed for MEDLINE]
Extract prepared from the bark of Cinnamomum cassia
Blume prevents glutamate-induced neuronal death in cultured cerebellar
Y, Goto H, Kogure T, Kohta K, Shintani
T, Itoh T, Terasawa
Department of Japanese Oriental Medicine, Faculty of Medicine, Toyama Medical and Pharmaceutical
University, 2630 Sugitani, Toyama 930-0194, Japan.
We studied the protective effect of a water extract from the bark of
Cinnamomum cassia Blume on glutamate-induced neuronal death by MTT assay and
its action on (45)Ca(2+) influx using cultured rat cerebellar granule cells.
In a dose-dependent manner, this extract (10(-5)-10(-4) g/mL) significantly protected
against glutamate-induced cell death and also inhibited glutamate-induced
(45)Ca(2+) influx. These results suggest that the bark of Cinnamomum
cassia has a protective effect on glutamate-induced neuronal death through the
inhibition of Ca(2+) influx. Copyright 2000 John Wiley & Sons, Ltd.
PMID: 10960905 [PubMed - indexed for MEDLINE]