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Retarding ALS Progression: An Experimental
Regimen (Created by Anthony G. Payne,
Ph.D.) This regimen was developed over time
and includes dietary, nutraceutical and dietary measures that have seemingly
slowed progression in nonfamilial ALS patients. These measures address some of
the major known biologic players in Lou Gehrig’s. In-a-nutshell, the
regimen.... Ř
Reduces or otherwise modulates
glutamate in motor neurons and astrocytes. Ř
Modulates calcium influx in motor
neurons, which in and of itself can cause apoptosis
(die-off). Ř
Lowers homocysteine when elevated
(Homocysteine apparently can become neurotoxic when elevated
significantly). Ř
Increases quinine reductase activity
in motor neurons and astrocytes, which helps lower or otherwise modulate
glutamate levels. Nutraceuticals
PREVAGEN – Rationale for use: Prevents
calcium influx and toxicity in neurons. Recommended 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. LITHIUM
OROTATE – Rational for use: Glutamate modulation in neurons. Recommended
use: Follow physician recommendations (Most ALS patient wind up taking 1 tablet
or more every 2 hours. High doses require testing to insure that toxicity does
not occur). NONI
– Rationale for use: Contains a potent Quinone reductase inducer – QR reduces
glutamate toxicity in cells. Recommended use: Juice should 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 – Rationale for use: Quinone reductase inducer in astrocytes (Lowers
glutamate). Recommended Dose: 1
tablet every two hours during the day and 1-2 tablets prior to bedtime. MEDIUM
CHAIN TRIGLYCERIDES (MCT) LIQUID OR SOFTGELS. Rational: A modicum of
research indicates that a high MFT diet may slows ALS. Recommended dose: Consult
a physician and possibly an R.D. (Registered Dietician) regarding creating an
MFT diet and supplement plan. NUTRACENE®- This time-release B-multiple
will help lower homocysteine, which is typically high in advanced ALS patients
and induces apoptosis (die-off) in neurons according to some lab
studies. FOR ALS PATIENTS WITH ACTIVE HUMAN
HERPES VIRUS 6 (HHV-6): If HHV-6 is suspect to be active,
there are a handful of natural compounds that might prove helpful: Non-Toxic NDGA (One
source: VIROX) and
Transfer Factor-HHV6
(One source: Contact
this company and ask) Pharmaceuticals (Prescribed
drugs)
DEPRENYL – Follow physician
instructions. Diet
Recommended Diet: Medium Chain Triglycerides Diet.
Rationale: There are many reasons the ketogenic or MCT diets can 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) Also: Drink
plenty of green tea (The ECGC proved neuroprotective in an animal model of ALS),
and consume lots of curry dishes (There are a wealth of anti-inflammatory
compounds in curry including turmeric). OTHER EXPERIMENTAL MEASURES FOLLOW
BELOW Disclaimer:
Statements made and products sold through the web sites mentioned have not been
evaluated by the US Food and Drug Administration. They are not intended to
diagnose, treat, cure, or prevent any disease. The information contained in this
regimen is provided for informational purposes only and should not be construed
as medical advice or instruction. Readers are advised to consult a licensed
health care professional concerning all matters related to their health and well
being.
Ciliary Neurotrophic Growth
Factor Expressing Cord Blood Stem Cells Researchers
have known for some time that ciliary neurotrophic growth factor (CNGF) prolongs
the survival of motor neurons (Animal models). And many of these have proposed
using CNGF to treat ALS. The problem lies in the fact that CNGF is a large
molecule that cannot get through the blood brain barrier. As
a result, many scientists have invested a great deal of time in
trying to figure out how to bypass the blood brain-barrier in order to get
CNGF into the CNS -- many by use of pumps and implantable, CNF-laden resins
and such (See the article below). My approach was simpler: Genetically
engineer cord blood mesenchymal or other cells to synthesize and express CNGF,
then catheter infuse them into an ALS patient’s CNS. These cells should live for
about 180 days and thus afford ALS patients the presence of this growth factor
on a fairly continuous basis for almost half a year. Subsequent infusions
should keep the process going. During
2006 genetics engineers working with stem cell clinical researcher Fernando
Ramirez Del Rio, M.D. (in Mexico) ran with my idea and produced a human
umbilical cord stem cell line that expresses ciliary neurotrophic growth factor.
Following animal experiments which indicated these
cells were safe, they were employed (in Mexico) to treat
advanced, dying ALS patients (An ethical choice all-things-considered). In the
weeks and months that followed many of those treated noted experiencing greater
energy, stamina, balance and motor function. One very advanced ALS patient
reported recovering some function in his previously immobile lower limbs.
Anthony
G. Payne, Ph.D. NOTE:
An additional line of cord blood (mesenchymal) stem cells was created which
expresses Vascular Endothelial Growth Factor (VEGF) -- a growth factor which
published research indicates may benefit ALS. These cells have not been used in
any ALS patients to-date (February 2008). They were, however, infused into
people with heart and liver diseases that would tend to respond favorably to
VEGF. No side-effects were noted and some clinical benefits were
documented.
http://www.jneurosci.org/cgi/reprint/22/21/9221 MDA
GRANTEE HAS HIGH-SPEED PLAN FOR FINDING ALS THERAPIES "There's
been a lot of poison in the air about neurotrophic factors," says neurologist
and neuroscientist Ralph Kuncl, an MDA grantee at Johns Hopkins University
Medical Center in Baltimore . "And that's too bad, because I think that, hidden
in this group, are some of the most potent agents we have." The
question for Kuncl and other researchers is how to find them and use them as
therapeutic agents in ALS. Kuncl
believes in the future of neurotrophic factors, proteins produced by the body in
or near nerve cells (neurons) that help keep these cells alive under a variety
of adverse conditions, including disease, injury and a natural "pruning" process
that occurs during embryonic development. He
leads a team that's testing new neurotrophic factors and has had success with
two new ones -- PEDF (pigment epithelium-derived factor) and neurturin. Kuncl
has also developed some new ways of testing the effectiveness of existing
neurotrophic factors. Neurotrophic
factors have been important in research on ALS and other neurodegenerative
diseases for several years. But results in clinical trials haven't lived up to
expectations derived from laboratory models. Part
of the reason, in Kuncl's view, is the inadequacy of these laboratory models in
predicting what will actually happen when neurotrophic factors are tried in
people. A
Realistic Environment One
way to study a substance for its effects on cells is to apply it to the cells
(for example, to motor neurons, which are the muscle-controlling nerve cells
lost in ALS) in a laboratory dish -- a "cell culture model" or "cell culture
system." Neurons in a laboratory culture can be injured by a variety of toxins
and then given various substances to see how well they "rescue" the neurons from
the damaging agent. This
method, Kuncl says, has its limitations. Cells in culture are like fish out of
water; they don't live very long and outside their natural environment their
behavior isn't necessarily usual for them. Because of their short life span,
cells in a culture dish can't be used to study chronic conditions like ALS,
where damage occurs slowly over time. Other
scientists study cells in animal models of a disease. Mouse models of ALS
include the SOD1 transgenic mouse, which has a genetic mutation known to cause
ALS in humans, and the wobbler mouse, which has a genetic mutation that produces
a disease resembling ALS. But
intact animals also have their limitations, Kuncl points out. Even with
state-of-the-art imaging techniques, it's impossible to see everything that's
going on at the cellular level inside a live animal. And, as with humans, there
are so many biochemical processes going on at once inside the animal that it's
difficult to sort out what's causing what. It's also hard to say whether the
animal has the same disease that human patients do. About
seven years ago, Kuncl's group at Johns Hopkins developed an "organotypic" model
for studying neurodegenerative diseases. The system consists of thick slices of
the spinal cords of rats, including all the connections between the neurons and
their supporting cells, the glia. Investigators can manipulate the cells with
different damaging agents (for example, exposing them to too much glutamate,
which is almost certainly a factor in many cases of human ALS). This
approach "provides you with an environment in which motor neurons normally live
and that's much more like real life," Kuncl says. Proof
is in the Pudding Kuncl
admits that his claims are theoretical. Proof will depend on finding a
correlation between his organotypic model and results of clinical trials on
humans. Kuncl
believes that, if you subtract for the "delivery factor" (the difficulty of
delivering neurotrophic factors to the motor neurons in animals or humans), the
results seen in his organotypic model pretty well match what you see in clinical
trials of neurotrophic factors. That
correlation indicates that the substances tested in his model have promising
neuron preservation capabilities, he says. If scientists are sure a drug can
rescue cells if it can reach them, it's worthwhile developing a good delivery
system and testing it in humans, an effort that can cost millions of dollars and
years of time. "By
any systemic administration, you're counting on the nerve terminals down in the
muscle to gobble up this stuff and transport a small fraction of it up [to the
neuron]," Kuncl says. "In order to do that, you have to give massive amounts,
which is both costly and risky, leading to systemic side effects, such as
occurred in the CNTF [ciliary neurotrophic factor] trial, and production of
antibodies, which could diminish the [therapeutic]
effect." One
way to get around the delivery stumbling block would be to implant genes for a
neurotrophic factor at spots where they're likely to be able to get the factor
to the motor neurons, Kuncl says. Another
method would be "to implant the factors or their genetic machinery in a wafer or
resin that would continually leak it out into the nervous
system." Kuncl
says implanting such substances near the spinal cord would probably be effective
because "most of the disability in ALS is lower motor neuron, which is spinal
cord, and most of the chance for reversibility by protecting motor neurons and
enhancing sprouting [growth of extensions from the neurons] is at the lower
motor neuron." New
Factors in the Pipeline Kuncl's
team published its PEDF results in the July issue of the Journal of
Neuropathology and Experimental Neurology and its neurturin results in the May
issue of Molecular and Cellular Neuroscience. Either
of these substances used alone in the organotypic culture model led to
"virtually 100 percent survival over a course of two months," Kuncl says, under
neuron-damaging conditions "when otherwise half the motor neurons or more would
have been gone." When
two such factors are combined, the results can be "even more spectacular," he
says. Kuncl
is particularly enthusiastic about PEDF because it may have certain advantages
over other existing factors. For
one thing, its effects aren't limited to its success as a neurotrophic factor.
Recent research has uncovered a potential role for PEDF in preventing blindness
in common conditions in which too many blood vessels grow in the retina or other
parts of the eye. This fortuitous finding may make PEDF a hot commodity for drug
companies because of its potentially broad commercial uses. Another
advantage of PEDF is the small size of some of its active
parts. Their
size, Kuncl says, will make administration easier, whether a gene therapy or a
drug therapy approach is used. Small molecules are much more likely to cross
natural barriers and enter the nervous system, even if they're administered
systemically, he says. Kuncl
is careful to say that the discovery of PEDF and neurturin as potential drugs
for ALS is still a long way from the clinic. "This discovery with PEDF allows it
to enter the pipeline," he says, "but the pipeline is long." http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1859845&blobtype=pdf http://www.jneurosci.org/cgi/reprint/22/21/9221 Am
J Pathol.
2006 Aug;169(2):584-98.
Links
Continued
administration of ciliary neurotrophic factor protects mice from inflammatory
pathology in experimental autoimmune encephalomyelitis. .
Departement
de Pharmacologie, Pavillon Roger Gaudry, 2900 Edouard-Montpetit, Montreal , QC
H3T 1J4 , Canada . jf.gauchat@umontreal.ca. Multiple
sclerosis is an inflammatory disease of the central nervous system that leads to
loss of myelin and oligodendrocytes and damage to axons. We show that daily
administration (days 8 to 24) of murine ciliary neurotrophic factor (CNTF), a
neurotrophic factor that has been described as a survival and differentiation
factor for neurons and oligodendrocytes, significantly ameliorates the clinical
course of a mouse model of multiple sclerosis. In the acute phase of
experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte
glycoprotein peptide 35-55, treatment with CNTF did not change the peripheral
immune response but did reduce the number of perivascular infiltrates and T
cells and the level of diffuse microglial activation in spinal cord. Blood brain
barrier permeability was significantly reduced in CNTF-treated animals.
Beneficial effects of CNTF did not persist after it was withdrawn. After
cessation of CNTF treatment, inflammation and symptoms returned to control
levels. However, slight but significantly higher numbers of oligodendrocytes,
NG2-positive cells, axons, and neurons were observed in mice that had been
treated with high concentrations of CNTF. Our results show that CNTF inhibits
inflammation in the spinal cord, resulting in amelioration of the clinical
course of experimental autoimmune encephalomyelitis during time of
treatment. PMID:
16877358 [PubMed - in process] http://www.uvm.edu/annb/faculty/PDFs/283.pdf Axonal Remyelination by Cord Blood
Stem Cells after Spinal Cord Injury Abstract Human
umbilical cord blood stem cells (hUCB) hold great promise for therapeutic repair
after spinal cord injury (SCI). Here, we present our preliminary investigations
on axonal remyelination of injured spinal cord by transplanted hUCB. Adult male
rats were subjected to moderate SCI using NYU Impactor, and hUCB were grafted
into the site of injury one week after SCI. Immunohistochemical data provides evidence of differentiation
of hUCB into several neural phenotypes including neurons, oligodendrocytes and
astrocytes. Ultrastructural analysis of axons reveals that hUCB form
morphologically normal appearing myelin sheaths around axons in the injured
areas of spinal cord. Colocalization studies prove that oligodendrocytes derived
from hUCB secrete neurotrophic hormones neurotrophin-3 (NT3) and brain-derived
neurotrophic factor (BDNF). Cord blood stem cells aid in the synthesis of myelin
basic protein (MBP) and proteolipid protein (PLP) of myelin in the injured
areas, thereby facilitating the process of remyelination. Elevated levels of
mRNA expression were observed for NT3, BDNF, MBP and PLP in hUCB-treated rats as
revealed by fluorescent in situ hybridization (FISH) analysis. Recovery
of hind limb locomotor function was also significantly enhanced in the
hUCB-treated rats based on Basso-Beattie-Bresnahan (BBB) scores assessed 14 d
after transplantation. These findings demonstrate that hUCB, when transplanted
into the spinal cord 7 days after weight-drop injury, survive for at least 2
weeks, differentiate into oligodendrocytes and neurons, and enable improved
locomotor function. Therefore, hUCB facilitate functional recovery after
moderate SCI and may prove to be a useful therapeutic strategy to repair the
injured spinal cord. J Neurosci. 2007 Jul 4;27(27):7094-104. Activation of
astrocytes by CNTF induces metabolic plasticity and increases resistance to
metabolic insults.
Escartin C, Pierre K, Colin A, Brouillet E, Delzescaux T, Guillermier M, Dhenain M, Déglon N, Hantraye P, Pellerin L, Bonvento G. High energy demands of neurons make them vulnerable to adverse effects of energy impairment. Recently, astrocytes were shown to regulate the flux of energy substrates to neurons. In pathological situations, astrocytes are activated but the consequences on brain energy metabolism are still poorly characterized. We found that local lentiviral-mediated gene transfer of ciliary neurotrophic factor (CNTF), a cytokine known to activate astrocytes, induced a stable decrease in the glycolytic flux in the rat striatum in vivo as measured by 2-[18F]-2-deoxy-D-glucose autoradiography and micro-positron emission tomography imaging. The activity of the mitochondrial complex IV enzyme cytochrome oxidase was not modified, suggesting maintenance of downstream oxidative steps of energy production. CNTF significantly increased the phosphorylation level of the intracellular energy sensor AMP-activated protein kinase (AMPK), supporting a specific reorganization of brain energy pathways. Indeed, we found that different key enzymes/transporters of fatty acids beta-oxidation and ketolysis were overexpressed by CNTF-activated astrocytes within the striatum. In primary striatal neuron/astrocyte mixed cultures exposed to CNTF, the AMPK pathway was also activated, and the rate of oxidation of fatty acids and ketone bodies was significantly enhanced. This metabolic plasticity conferred partial glial and neuronal protection against prolonged palmitate exposure and glycolysis inhibition. We conclude that CNTF-activated astrocytes may have a strong protective potential to face severe metabolic insults. PMID: 17611262 J Neurochem. 2008 Jan 17 Vascular
endothelial growth factor protects spinal cord motoneurons against
glutamate-induced excitotoxicity via phosphatidylinositol
3-kinase.
Tolosa L, Mir M, Asensio VJ, Olmos G, Lladó J. Grup de Neurobiologia Cel·lular, Departament de Biologia, Institut Universitari d’Investigacions en Cičncies de la Salut (IUNICS), Universitat de les Illes Balears, Palma de Mallorca, Spain. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective death of motoneurons. Recently, vascular endothelial growth factor (VEGF) has been identified as a neurotrophic factor and has been implicated in the mechanisms of pathogenesis of ALS and other neurological diseases. The potential neuroprotective effects of VEGF in a rat spinal cord organotypic culture were studied in a model of chronic glutamate excitotoxicity in which glutamate transporters are inhibited by threohydroxyaspartate (THA). Particularly, we focused on the effects of VEGF in the survival and vulnerability to excitotoxicity of spinal cord motoneurons. VEGF receptor-2 was present on spinal cord neurons, including motoneurons. Chronic (3 weeks) treatment with THA induced a significant loss of motoneurons that was inhibited by co-exposure to VEGF (50 ng/mL). VEGF activated the phosphatidylinositol 3-kinase/Akt (PI3-K/Akt) signal transduction pathway in the spinal cord cultures, and the effect on motoneuron survival was fully reversed by the specific PI3-K inhibitor, LY294002. VEGF also prevented the down-regulation of Bcl-2 and survivin, two proteins implicated in anti-apoptotic and/or anti-excitotoxic effects, after THA exposure. Together, these findings indicate that VEGF has neuroprotective effects in rat spinal cord against chronic glutamate excitotoxicity by activating the PI3-K/Akt signal transduction pathway and also reinforce the hypothesis of the potential therapeutic effects of VEGF in the prevention of motoneuron degeneration in human ALS. PMID: 18182045 Disclaimer:
Statements made and products sold through the web sites mentioned have not been
evaluated by the US Food and Drug Administration. They are not intended to
diagnose, treat, cure, or prevent any disease. The information contained in this
regimen is provided for informational purposes only and should not be construed
as medical advice or instruction. Readers are advised to consult a licensed
health care professional concerning all matters related to their health and well
being.
Cord Blood Serum Bottom
of Form Cord
blood serum is rich in growth factors that might ameliorate ALS. When cord blood
was transfused into ALS patients a few years back in Atlanta, Georgia by
maverick physician, Dr. Mitchell Ghen, many of the patients did show benefit
(See Something Is
Amiss) It is my contention that it was not the stem cells in the cord
blood, but the growth factors that helped pull off this medical feat. As
such, an IV infusion of cord blood serum (30 mL) or so should have salutary
effects in ALS.
Other Experimental Approaches Beta Lactam Antibiotics – Glutamate
Transporter Function
Rationale: Many researchers have found evidence that the
glutamate transporter function (EAAC1) in the motor neurons of ALS patients
fails to function properly which causes glutamate to accumulate, something
that can lead to (motor neuron) die-off. Interestingly, the antibiotic
ceftriaxone has been shown to increase expression of this transporter in animal
models (The transporter is GTL1 in rats – EAAC1 in humans). The NIH has funded a study (see below) to test the effects of
this antibiotic given via IV drip on ALS patients. The one drawback of using ceftriaxone IV is side-effects.
They can fairly onerous. One alternative might be slow release Keflex. This is a
cephalosporin albeit not identical structurally to ceftriaxone. However, the
core of all the cephalosporins is the same and it is this which may be
increasing expression of the glutamate transporter GTL1 in animals (EEAC1 in
human). Interestingly, some ALS patients I’ve mentioned this too went
to their primary care physician, got scripts for Keflex slow release, and have
begun taking this on a daily basis. Most appear to be slowly gaining energy.
Placebo effect or is the core molecule doing the trick? Either way, improvements
are occurring which for these dying ALS patients, is a Godsend. http://clinicaltrials.gov/ct/show/NCT00349622?order=1
– NIH Phase III clinical trial involving IVs of the (cephalosporin) ceftriaxone
recruiting now. "It is known that nerve cells called motor neurons die in the
brains and spinal cords of people with amyotrophic lateral sclerosis (ALS).
However, the cause of this cell death is unknown. Researchers think that
increased levels of a chemical called “glutamate” may be related to the cell
death. For this reason researchers want to study drugs that decrease glutamate
levels near nerves. Ceftriaxone—a semi-synthetic, third generation cephalosporin
antibiotic—may increase the level of a protein that decreases glutamate levels
near nerves. Studies of ceftriaxone in the laboratory suggest that it may
protect motor neurons from injury." http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1074355&blobtype=pdf
– "Beta-Lactam antibiotics offer neuroprotection by increasing glutamate
transporter expression," Jeffrey D. Rothstein et al, Nature, Vol. 433, 6 January
2005, pp. 73-77 v
Creatine
Rationale: May help reduce glutamate levels in the CNS of ALS
sufferers. http://clinicaltrials.gov/ct/show/NCT00355576?order=1
– NIH funded clinical trial involving creatine, minocycline and celecoxib One
doc, Dr. Lynn Myers suggests taking 15-20 grams per day (divided doses) for one
week, then dropping down to 5 grams daily (Again, divided doses). He recommends
"Creatine PowerTabs" – as they are premeasured to make taking high doses easier
(Albeit pure powder forms are available also for those who cannot readily
swallow tablets or such). http://www.nucare.com/creatpow.html (I have no
commercial or other ties to either Dr. Myers or this product)
v
Sodium
Phenylbutyrate
Something that might complement this regimen: Sodium
Phenylbutyrate. http://www.drugs.com/cons/Sodium_Phenylbutyrate.html
- Sodium Phenylbutyrate http://www.alsa.org/patient/drug.cfm?id=629
http://www.als.net/articles/articleDetail.asp?articleID=4538 http://clinicaltrials.gov/show/NCT00107770 -
NIH funded clinical trial – SP. Mechanism of action discussed on this
website. v
Low Methionine
Diet
Rationale:
There is some very tentative evidence – strictly from Petri Dish studies – that
methyl groups may inhibit glutamate transporters in motor neurons (Abstract
below). If so, it is conceivable that a low methionine diet might set the stage
for removal of some of the methyl groups in motor neurons that are inhibiting
glutamate transporter function.
http://www.hcusupport.com/diet.htm v
DMSO +
Aminoguanadine
Background: The
action of serofendic acid -- which was discovered in fetal calf serum by
Japanese researchers (abstracts and such follow below) -- appears to reduce
glutamate toxicity in neurons by attenuating the neuron-wrecking action of
Nitric Oxide (NO). My spin:
Serofendic acid isn't available for human use at this time, but there are some
compounds that appear to have a similar action. One is DMSO (dimethyl sulfoxide)
-- a chemical solvent that is used by some doctors in IV and oral form for
addressing various health challenges (It is FDA approved for interstitial
cystitis). The DMSO molecule is part of serofendic acid
actually. Also,
aminoguanadine lowers iNO (inducible nitric oxide) in the CNS -- which would
complement the action of DMSO. Aminoguanadine is a prescription
drug. Anthony G. Payne,
Ph.D. Journal of
Pharmacology And Experimental Therapeutics Fast Forward
Serofendic Acid, a Sulfur-Containing
Diterpenoid Derived from Fetal Calf Serum, Attenuates Reactive Oxygen
Species-Induced Oxidative Stress in Cultured Striatal Neurons
Fumitaka Osakada,
Yuka Kawato, Toshiaki Kume, Hiroshi Katsuki, Hachiro Sugimoto, and Akinori
Akaike Department of Pharmacology, Graduate School of Pharmaceutical
Sciences, Kyoto University, Kyoto, Japan (F.O., Y.K., T.K., H.K., A.A.); and
Department of Neuroscience for Drug Discovery Research, Graduate School of
Pharmaceutical Sciences, Kyoto University, Kyoto, Japan (H.S.) We previously identified a novel endogenous substance,
serofendic acid, from a lipophilic extract of fetal calf serum.
Serofendic acid protects cultured cortical neurons against the
cytotoxicity of glutamate and nitric oxide. Here, we reported the
protective effect of serofendic acid on reactive oxygen
species-induced oxidative stress using primary rat striatal cultures.
In addition, we compared the neuroprotective effect and the
radical-scavenging activity of serofendic acid with those of dimethyl
sulfoxide (DMSO), because serofendic acid possesses a DMSO
structure. Paraquat caused neuronal death, which was inhibited by
a cell-permeable superoxide dismutase (SOD) mimetic,
Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (Mn-TBAP); a
cell-permeable SOD/catalase mimetic, EUK-134 [manganese 3-methoxy
N,N'-bis(salicylidene)ethylenediamine chloride]; and a
ferrous ion chelator, 2,2'-dipyridyl, in rat striatal cultures.
Serofendic acid (10–100 µM) suppressed the neurotoxicity of paraquat,
whereas DMSO (10–100 µM) did not. By contrast, higher concentrations
(30–300 mM) of DMSO ameliorated the paraquat-induced cell death.
Furthermore, H2O2 induced neurotoxicity, which
was prevented by EUK-134 and 2,2'-dipyridyl. Serofendic acid (10–100
µM) also protected striatal neurons against the
H2O2-induced toxicity. Higher concentrations
(30–300 mM) of DMSO ameliorated H2O2-induced
neuronal death, whereas lower concentrations (10–100 µM) did not.
Electron spin resonance spectrometry with a spin-trapping technique
revealed that serofendic acid and DMSO had approximately the same
ability to inhibit the formation of the hydroxyl radical (·OH).
These
results suggest that the ·OH-scavenging activity of serofendic acid
is attributable to its DMSO structure and that the
remaining components such as the atisane structure play an important
role in eliciting neuroprotection at a concentration range of 10 to
100 µM. Neurosci
Lett.
2005 Aug 5;383(3):199-202. Epub 2005 Apr 25. Protective effect
of serofendic acid on glutamate-induced neurotoxicity in rat cultured motor
neurons. Department
of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University ,
46-29 Yoshida-shimoadachi-cho, Kyoto 606-8501, Japan. We
have previously reported that a sulfur-containing neuroprotective substance
named serofendic acid was purified and isolated from lipophilic extract of fetal
calf serum (FCS). In the present study, we investigated the effect of serofendic
acid on glutamate neurotoxicity using embryonic rat spinal cord culture. When
cultures were exposed to glutamate (20 microM) with a glutamate transporter
inhibitor L-trans-pyrrolidine-2,4-decarboxylate (PDC; 40 microM) for 24 h, motor
neurons were injured through both N-methyl-D-aspartate and
alpha-amino-3-hydroxy-5-methylisoxazole/kainate receptors. This glutamate
neurotoxicity was attenuated by nitric oxide (NO) synthase inhibitors.
Serofendic acid (0.1-5 microM) prevented glutamate neurotoxicity in a
concentration-dependent manner. S-Nitrosocysteine (SNOC; 10 microM), an NO
donor, induced motor neuronal death. Serofendic acid (5 microM) also prevented
SNOC-induced neurotoxicity. These results indicate that serofendic acid protects
cultured motor neurons from glutamate neurotoxicity by reducing the cytotoxic
action of NO.PMID: 15955411 PMID: 17185508 PMID: 16904319 PMID: 16806165 PMID: 16682316 PMID:
16682316 PMID:
16313102 PMID:
15955411 PMID: 15256723 PMID: 14607254 PMID: 14522357 PMID: 11867740 |