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A little more info..

jackd


1: Mult Scler. 2003 Dec;9(6):574-8.

Phosphodiesterase inhibitors suppress IL-12 production with microglia and T helper 1 development.

Suzumura A, Ito A, Mizuno T.
Department of Neuroimmunology, Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa, Nagoya 464-8601, Japan. suzumura@riem.nagoya-u.ac.jp

The effects of phosphodiesterase inhibitors (PDEIs) on interleukin (IL)-12 production by microglia, antigen-presenting cells in the central nervous system (CNS), were examined to learn how they affect T cell differentiation in the CNS. PDEIs significantly suppressed the microglial IL-12 production, as determined by reverse transcriptase-polymerase chain reaction for IL-12 p35 and p40 mRNA expression and by an ELISA specific for IL-12 functional heterodimer, p70. In addition, the PDEI ibudilast also suppressed interferon-gamma, but not IL-4 or IL-10, production by myelin oligodendrocyte glycoprotein (MOG)-specific T cells reactivated with MOG in the presence of microglia. Thus, PDEIs may also suppress differentiation of T helper 1 (Th1) in the CNS. PDEIs can be of use for future therapeutic strategy to treat Th1-mediated diseases, such as multiple sclerosis.

PMID: 14664469 [PubMed - indexed for MEDLINE]

1: Mult Scler. 2000 Feb;6(1):56-8. Links
Drop in relapse rate of MS by combination therapy of three different phosphodiesterase inhibitors.Suzumura A, Nakamuro T, Tamaru T, Takayanagi T.
Department of Neurology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-0813, Japan.

Phosphodiesterase inhibitors (PDEIs), when used in combination, synergistically suppress TNFalpha production by various cells and also suppress experimental demyelination at very low concentrations. We conducted a pilot study to determine whether the combination of three PDEIs suppresses the relapse of MS at the usual therapeutic doses. Of the 12 relapsing remitting MS, the mean relapse rate/year dropped remarkably (from 3.08+/-3.32 to 0.92+/-1.86) after PDEI treatment. Seven out of 12 (58.3%) were relapse-free in the follow up period (499+/-142 days).

The combination of three PDEIs can be safe and useful strategy for the future treatment of MS. - 58

jackD wrote:I believe in the BOTH theory.
http://home.ix.netcom.com/~jdalton/ms-two-stages.pdf

Hi Jack,
I liked the article and I also believe it's both.

I'm going to have to go back and read finn's first post in this thread because I'm not convinced that either autoimmune or non autoimmune's side of the argument requires or even benefits from a "versus" situation (regarding inflammation v neurodegeneration) as opposed to a "both" situation.

Bob

If you liked the article then you might want to consider an action plan..

jackD


1: J Pharmacol Exp Ther. 1989 Sep;250(3):1132-40.

Antioxidants protect against glutamate-induced cytotoxicity in a neuronal cell line.

Miyamoto M, Murphy TH, Schnaar RL, Coyle JT.

Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland.

The effects of reducing agents and antioxidants on L-Glutamate (Glu)-induced cytotoxicity were examined in the N18-RE-105 neuronal cell line. The cytotoxicity by Glu (1 and 10mM) was potentiated by exposure to growth medium containing a low concentration of cystine (5-100 microM), instead of the normal medium containing 200 microM cystine. In contrast, the toxicity was suppressed by increasing the cystine concentration to 500 to 1000 microM. Reducing agents, cysteine (30-1000 microM), dithiothreitol (10-250 microM) and glutathione (GSH, 10-1000 microM) also protected the cells against the cytotoxicity of 10 mM Glu in a concentration-dependent manner.

The antioxidants vitamin E (10-100 microM), idebenone (0.1-3 microM) and vinpocetine (10-100 microM) also provided marked protection against the cytotoxicity of Glu (10 mM) or quisqualate (1 mM). Antioxidants also prevented the delayed cell death caused by lowering the concentration of cystine in the medium to 5 microM. Incubation of the cells with 10 mM Glu caused a marked decrease in cellular GSH levels. Although cysteine and dithiothreitol prevented the GSH reduction caused by Glu, antioxidants did not. The cellular levels of oxidants were assessed using 2,7-dichlorofluorescin, a probe that accumulates within cells and is converted to a fluorescent product by oxidation. Glu (10 mM) caused a marked increase in such fluorescence, whereas vitamin E and idebenone reduced markedly the number of fluorescent cells to control levels even added with 10 mM Glu. These results indicate that oxidative stress due to loss of cellular levels of GSH is one mechanism whereby Glu/quisqualate exert cytotoxicity and suggest that centrally active antioxidants may reduce neuronal damage in pathologic conditions associated with excessive Glu release.

PMID: 2778712 [PubMed - indexed for MEDLINE]

The best Vitamin E should be VERY VERY heavy in tocotrienols. I take some PURE tocotrienols several times a day. Chek your pills NOW!!

jackD

tocotrienols neuroprotection

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1: J Neurochem. 2006 Sep;98(5):1474-86.

Characterization of the potent neuroprotective properties of the natural vitamin E alpha-tocotrienol.

Khanna S, Roy S, Parinandi NL, Maurer M, Sen CK.
Laboratory of Molecular Medicine, Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University Medical Center, Colombus, Ohio 43210, USA.

The natural vitamin E tocotrienols possess properties not shared by tocopherols. Nanomolar alpha-tocotrienol, not alpha-tocopherol, is potently neuroprotective. On a concentration basis, this finding represents the most potent of all biological functions exhibited by any natural vitamin E molecule. We sought to dissect the antioxidant-independent and -dependent neuroprotective properties of alpha-tocotrienol by using two different triggers of neurotoxicity, homocysteic acid (HCA) and linoleic acid. Both HCA and linoleic acid caused neurotoxicity with comparable features, such as increased ratio of oxidized to reduced glutathione GSSG/GSH, raised intracellular calcium concentration and compromised mitochondrial membrane potential. Mechanisms underlying HCA-induced neurodegeneration were comparable to those in the path implicated in glutamate-induced neurotoxicity. Inducible activation of c-Src and 12-lipoxygenase (12-Lox) represented early events in that pathway. Overexpression of active c-Src or 12-Lox sensitized cells to HCA-induced death. Nanomolar alpha-tocotrienol was protective. Knock-down of c-Src or 12-Lox attenuated HCA-induced neurotoxicity. Oxidative stress represented a late event in HCA-induced death. The observation that micromolar, but not nanomolar, alpha-tocotrienol functions as an antioxidant was verified in a model involving linoleic acid-induced oxidative stress and cell death. Oral supplementation of alpha-tocotrienol to humans results in a peak plasma concentration of 3 microm. Thus, oral alpha-tocotrienol may be neuroprotective by antioxidant-independent as well as antioxidant-dependent mechanisms.

PMID: 16923160 [PubMed - indexed for MEDLINE]


1: Ann N Y Acad Sci. 2004 Dec;1031:127-42.

Tocotrienol: the natural vitamin E to defend the nervous system?

Sen CK, Khanna S, Roy S.
Davis Heart & Lung Research Institute, 473 West 12th Avenue, The Ohio State University Medical Center, Columbus, Ohio 43210, USA. sen-1@medctr.osu.edu

Vitamin E is essential for normal neurological function. It is the major lipid-soluble, chain-breaking antioxidant in the body, protecting the integrity of membranes by inhibiting lipid peroxidation. Mostly on the basis of symptoms of primary vitamin E deficiency, it has been demonstrated that vitamin E has a central role in maintaining neurological structure and function. Orally supplemented vitamin E reaches the cerebrospinal fluid and brain. Vitamin E is a generic term for all tocopherols and their derivatives having the biological activity of RRR-alpha-tocopherol, the naturally occurring stereoisomer compounds with vitamin E activity. In nature, eight substances have been found to have vitamin E activity: alpha-, beta-, gamma- and delta-tocopherol; and alpha-, beta-, gamma- and delta-tocotrienol. Often, the term vitamin E is synonymously used with alpha-tocopherol. Tocotrienols, formerly known as zeta, , or eta-tocopherols, are similar to tocopherols except that they have an isoprenoid tail with three unsaturation points instead of a saturated phytyl tail. Although tocopherols are predominantly found in corn, soybean, and olive oils, tocotrienols are particularly rich in palm, rice bran, and barley oils. Tocotrienols possess powerful antioxidant, anticancer, and cholesterol-lowering properties. Recently, we have observed that alpha-tocotrienol is multi-fold more potent than alpha-tocopherol in protecting HT4 and primary neuronal cells against toxicity induced by glutamate as well as by a number of other toxins. At nanomolar concentration, tocotrienol, but not tocopherol, completely protected neurons by an antioxidant-independent mechanism. Our current work identifies two major targets of tocotrienol in the neuron: c-Src kinase and 12-lipoxygenase. Dietary supplementation studies have established that tocotrienol, fed orally, does reach the brain. The current findings point towards tocotrienol as a potent neuroprotective form of natural vitamin E.

PMID: 15753140 [PubMed - indexed for MEDLINE]


1: Neuropharmacology. 2004 Nov;47(6):904-15.

Alpha-tocotrienol provides the most potent neuroprotection among vitamin E analogs on cultured striatal neurons.

Osakada F, Hashino A, Kume T, Katsuki H, Kaneko S, Akaike A.
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.

Oxidative stress and apoptosis play pivotal roles in the pathogenesis of neurodegenerative diseases. We investigated the effects of vitamin E analogs on oxidative stress and apoptosis using primary neuronal cultures of rat striatum. A tocotrienol-rich fraction of edible oil derived from palm oil (Tocomin 50%), which contains alpha-tocopherol, and alpha-, gamma- and delta-tocotrienols, significantly inhibited hydrogen peroxide (H2O2)-induced neuronal death. Each of the tocotrienols, purified from Tocomin 50% by high-performance liquid chromatography, significantly attenuated H2O2-induced neurotoxicity, whereas alpha-tocopherol did not. alpha-, gamma- and delta-Tocotrienols also provided significant protection against the cytotoxicity of a superoxide donor, paraquat, and nitric oxide donors, S-nitrosocysteine and 3-morpholinosydnonimine. Moreover, tocotrienols blocked oxidative stress-mediated cell death with apoptotic DNA fragmentation caused by an inhibitor of glutathione synthesis, L-buthionine-[S,R]-sulfoximine. In addition, alpha-tocotrienol, but not gamma- or delta-tocotrienol, prevented oxidative stress-independent apoptotic cell death, DNA cleavage and nuclear morphological changes induced by a non-specific protein kinase inhibitor, staurosporine. These findings suggest that alpha-tocotrienol can exert anti-apoptotic neuroprotective action independently of its antioxidant property. Among the vitamin E analogs examined, alpha-tocotrienol exhibited the most potent neuroprotective actions in rat striatal cultures.

PMID: 15527824 [PubMed - indexed for MEDLINE]

finn wrote:What we know almost for sure at the moment:

• Inflammation, abnormal T-cell activity, demyelination and axonal degeneration are all present in the pathogenesis of MS.
• Clinical relapses and reverseable disability are caused by demyelination.
• Active lesions shown in MRI are caused by inflammation, but removing MRI-activity with anti-inflammatory drugs doesn't necessarily prevent clinical relapses and the progression of disability.
• Most of the permanent disability is probably caused by axonal degenaration. Normally our system doesn't allow axons to regenarate.
• (Fortunately) the progression of permanent disability in MS may be much slower process than earlier thought.

Hi finn,
First, I'm assuming you are referring to relapses and remissions (in the red).
I know demelination and remyelination seems to be the "commonly accepted" explanation for the coming and going of symptoms in the relapsing/remitting phase but what do you personally think? Aren't you a little uncomfortable about that one? Not that there is any shortage of square pegs halfway pounded into round holes in MS "conventional wisdom" but that one has always seemed blatantly illogical to me.
Bob

Bob

Bob,

Lyon wrote:I'm not convinced that either autoimmune or non autoimmune's side of the argument requires or even benefits from a "versus" situation (regarding inflammation v neurodegeneration) as opposed to a "both" situation.

I'd say you are referring to two processes that can be at least partly separated:

Autoimmune vs. non autoimmune

• This is a question of the origin of inflammation.
• Autoimmune means that the immune system attacks against body's own tissue for a reason that is not known.
• Non autoimmune means that there is a reason for the immune reaction. Either the immune system attacks directly against a foreign and/or harmful pathogen, or the inflammation is a normal reaction to a tissue damage that has already occured.

Inflammation vs. neurodegeneration

• This is a question of the primary pathological process of MS.
• There are several (more or less likely) ways to see the pathological process:
  • Inflammation causes demyelination, and eventually demyelination leads to axonal degeneration (traditional hypothesis).
  • MS starts as an inflammatory disease with a neurodegenerative component, but can change into a primary neurodegenerative disease (two stage model)
  • Neurodegeneration is the primary process from the onset of the disease, and inflammation is a reaction to it (my favourite theory).
  • Inflammation and neurodegeneration are seperate and independent processes.
  • etc?

IMO, when we talk about therapies, this is definitely a "versus" situation. If MS was purely an inflammatory disease, its progression could be halted with a powerful anti-inflammatory treatment. If it it was a neurodegenerative disease, it would require a neuroprotective treatment to prevent it from progressing. In a neurodegenerative disease a neuroprotective treatment could also prevent inflammation.

Lyon wrote:I know demelination and remyelination seems to be the "commonly accepted" explanation for the coming and going of symptoms in the relapsing/remitting phase but what do you personally think? Aren't you a little uncomfortable about that one?

Actually, I'm not :-) In this post I speculated like this:

Anyway, if MS was primarily a neurodegerative disease that starts with changes in gray matter, I suppose one could assume that

• since axons in white matter are extensions of those in gray matter, negative changes in gray matter might make them produce too much glutamate in white matter.
• central nervous system might even try to compensate weakened connectivity caused by axonal degeneration with producing more neurotransmitter glutamate.
• too much glutamate might be able to kill oligodendrocytes (myelin making cells), and maybe the cell death could cause inflammation seen in white matter lesions.
• a relapse in RRMS might be caused by temporary overproduction of glutamate followed by death of oligodendrocytes and/or inflammation in white matter. And maybe a remission occurs only if central nervous system is able to rewire or reorganize itself (in fMRI studies it has been shown that performing even a simple task requires more activity in MS brain than in healthy brain).

My speculation was based on a recent study suggesting that axons release glutamate also in the white matter.

-finn

Perhaps the Fins do have some value.

http://news.bbc.co.uk/1/hi/health/6266498.stm

finn wrote:IMO, when we talk about therapies, this is definitely a "versus" situation. If MS was purely an inflammatory disease, its progression could be halted with a powerful anti-inflammatory treatment. If it it was a neurodegenerative disease, it would require a neuroprotective treatment to prevent it from progressing. In a neurodegenerative disease a neuroprotective treatment could also prevent inflammation.

Hi finn,
Thanks for the complete explanation. I'm understanding more clearly where you're coming from, but I have to agree with Ian that's it's pretty hard to debate these situations which science knows so little about and couldn't hope to prove.

To further my understanding....above, I assume you are referring to therapies directed specifically and exclusively at the cause? Otherwise I'd have to disagree because as you've already admitted and is commonly accepted that MS involves both inflammation and neurodegeneration.

I think this specific point is what is keeping some of us from understanding where you're coming from with this thread.

To clarify, you're saying

If MS was purely an inflammatory disease,
If it it was a neurodegenerative disease,

and the point is that it's most assuredly not either, it's both. With that being the case I have to assume that you are talking about which specifically "initiates" and/or "drives" the MS process?
Bob

Ian,

bromley wrote:Perhaps the Fins do have some value.

Well, at least we usually try to spell more carefully than some Englishmen seem to do.

Seriously, thanks for sharing that piece of news from Finland in English. I have it in my files in Finnish, and I've been planning to translate and post it somewhere, but I've been too lazy to actually do it.

Bob,

Lyon wrote:I have to agree with Ian that's it's pretty hard to debate these situations which science knows so little about and couldn't hope to prove.

It may be hard, but I find it also interesting because there are so many options open. Remember, nobady forces you to join the debate.

Lyon wrote:To further my understanding....above, I assume you are referring to therapies directed specifically and exclusively at the cause? Otherwise I'd have to disagree because as you've already admitted and is commonly accepted that MS involves both inflammation and neurodegeneration.

Let me put it this way: If MS was a neurodegenerative disease and inflammation was a reaction to neurodegeneration, don't you think it would be possible that preventing neurodegeneration would stop inflammation, too?

Lyon wrote:To clarify, you're saying

If MS was purely an inflammatory disease,
If it it was a neurodegenerative disease,

and the point is that it's most assuredly not either, it's both. With that being the case I have to assume that you are talking about which specifically "initiates" and/or "drives" the MS process?

C'mon, does my English suck that bad? Or are you just nitpicking? In any case, the answer is "yes".

-finn.

finn wrote:

Lyon wrote:I have to agree with Ian that's it's pretty hard to debate these situations which science knows so little about and couldn't hope to prove.

It may be hard, but I find it also interesting because there are so many options open. Remember, nobody forces you to join the debate.

One of my wife's uncle's was a finn and one of the nicest guys I've ever known, so I'm confident that all Finns aren't asses.

finn wrote:Let me put it this way: If MS was a neurodegenerative disease and inflammation was a reaction to neurodegeneration, don't you think it would be possible that preventing neurodegeneration would stop inflammation, too?

Good! I finally understand and I think I've always agreed. While there is no way to confirm whether neurodegeneration or inflammation come first, my point has always been that we need to attack the MS process at a point even prior to that.

Of course by the time ANYONE is diagnosed with MS significant neurodegeneration has already occured so treatments aimed in that direction are essential but my point is that the first priority is to stop the disease process and as knowledge accumulates it will later be determined if you and I part ways at this juncture.

As an "autoimmune" guy, I think the results we've seen from removing exclusively something as specific as the "myelin reactive T cells" is proof positive that those T cells had been responsible for BOTH the neurodegeneration and the inflammation. I'd like to know if Opexa has noticed tightening of the bbb after treatment, which would signify effect on the entirety of MS as it's been defined to this point but that info doesn't seem available.

finn wrote:C'mon, does my English suck that bad? Or are you just nitpicking? In any case, the answer is "yes".

That's not the issue. English is my first language but these things we discuss can be so complicated with so many ways of looking at them that I wanted to understand your EXACT meaning. Sometimes that involves asking questions. That doesn't mean that you didn't explain it correctly and it doesn't mean I have a problem understanding things.

Lighten up! This is a discussion board where things are questioned and challenged and at that point I wasn't doing either, I was trying to understand exactly what you meant.

Bob

Lyon wrote:As an "autoimmune" guy, I think the results we've seen from removing exclusively something as specific as the "myelin reactive T cells" is proof positive that those T cells had been responsible for BOTH the neurodegeneration and the inflammation.

ooooo... that's a big call. What mechanism do you see the T-Cells using to degenerate the nerve fibres before attacking the myelin?

Hi Cure,
I might have lied to finn, maybe I am hard of understanding.

What nerve fibers are you talking about?

What mechanism do you see the T-Cells using to degenerate the nerve fibres before attacking the myelin?

Bob

Lyon wrote:What nerve fibers are you talking about?

I was using the term as a general pointer to the neurons, coated in myelin, that are being degenerated BEFORE the myelin is attacked/inflamed.

So to clarify my question, you have implied that you feel the T-Cells are causing both neurodegeneration and inflammation independently. The implication being that they are also causing neuron death before the myelin is attacked. My question is how do you see this occurring?

CureOrBust wrote:I was using the term as a general pointer to the neurons, coated in myelin, that are being degenerated BEFORE the myelin is attacked/inflamed.

So to clarify my question, you have implied that you feel the T-Cells are causing both neurodegeneration and inflammation independently. The implication being that they are also causing neuron death before the myelin is attacked. My question is how do you see this occurring?

Hi Cure,
Sometimes I think you do this on purpose to frustrate me ......but on the chance that I'm mistaken.

Possibly you are referring to the axon which is coated in myelin? Because the neuron is the entire unit.

If you are referring to the axon please remember that my initial statement was

Extremely good looking and intelligent Lyon wrote:As an "autoimmune" guy, I think the results we've seen from removing exclusively something as specific as the "myelin reactive T cells" is proof positive that those T cells had been responsible for BOTH the neurodegeneration and the inflammation.

and your reply was

Cure or drive Lyon friggin' nuts wrote:you have implied that you feel the T-Cells are causing both neurodegeneration and inflammation independently. The implication being that they are also causing neuron (=axon?) death before the myelin is attacked.

My statement referred to the wisdom of deleting the immune attack (removing the myelin reactive T cells) prior to implementation of both neurodegeneration or inflammation.

I'm not sure how you came to the conclusion that my implication was that "they" (myelin reactive T cells?) are causing neuron (axon?) death before the myelin is attacked because my only inference was that it's wise to remove those "self" reactive T cells at a point prior to an attack on either the myelin or the axon.....before inflammation or neurodegeneration cause a problem.

Regarding my opinion as to whether the myelin or axon are attacked first, "entia non sunt multiplicanda praeter necessitatem", the simplest and most likely scenario is that the myelin is attacked first and therein lies my opinion.

I'm glad you didn't pick on my parasites....now THAT is frustrating!

Bob

Double post on my part that I hadn't noticed until now.