NeuroTalk Support Groups - More symptoms even on Avonex

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More symptoms even on Avonex

I have been on Avonex for 17 weeks now but I am still experiencing new symptoms. Especially in the past month.

My doctor had me cut my Avonex back to 1/2 about a month ago because of the side effects.

I THOUGHT I had been taking half dose but found out from the pharmacist that I have actually been taking 3/4 dose.

That was my fault for not understand where the half way mark is at.

But at least my side effects of Avonex are becoming less even on the 3/4 dose.

Anyway, I am concerned about these newest symptoms, intense leg spasms and hand spasm, even though I am on Avonex. The ON I started in January is getting better.

How does a doctor decide if you have RRMS or one of the others? In the past I have had clear onset and then recovery, this time I am wondering what is going on.

Thanks,
LA

LA,

You should have a long discussion about this with your neurologist face to face. The neurologist needs to know exactly how things are going at this time, even though you met with him recently.

I hope it works out for you.

-Vic

Hi Vic,
Thanks. I will be seeing my MS doctor on July 1st.

My doctor is good about listening so I will be asking some more questions at this appointment.

I'm just so darn tired and worried about some of these newer symptoms. I slept until 11:45 this morning and am ready to go back to be and it is only 5:38. I think the spasms in my leg at night are keeping me from sleeping well.

Sleeping in that long today was sure nice though!

LA

I regret to tell you this BUT AVONEX takes about 4 to 6 months to fully "kick in" and give you favorable reduction of symptoms.

Also Avonex is not effective during major relapses. I think that starting Avonex during an attack may make things a tad worse for three reasons 1 your hyper-active immune system may react to the Avonex and 2 the stress related to the starting of the shots and three the Avonex symptoms may make you "feel sick".

Most folks do not want to explore how MS progreses but are more concerned about the "ultimate cause of MS" (whatever that is).

I can provide some detail info on this but you I must warn you that it will contain SOME BIG WORDS!!!!

Most MS folks seem to panic and beg me to stop-- so I will ask you to actually request me to continue before I provide the detail info.

I find unless you are really on a QUEST FOR INFO that most MS folks will not even read my info. Almost 100% of this "stuff" comes from NLM-NIH PubMed.

I would give you some GREAT links but I am in the under 10 group..
jackD

P.S. I was on AVONEX for last 10 years. Results VERY GOOD!!

In RR MS the MMP-9 and friends do a LOT of the damage. They cut a hole in the BBB - Blood Brain Barrier then enter along with a LOT of other "things that do not belong inside" and then the MMP-9s cut the mylin into three basic components that the other folks dine on.

In addition they (the mmp-9s) like to destroy/"kill" Avonex!!!

Quote:

jackD welcome! I like your journal details. Enjoyed your explanation too. Thank you. It won't be long before you can post urls.

What is a MMP?? Some comments

Simply put MMPs are a family of about 27 (mmp-1 to MMP-27) enzymes that share a common characteristic function and structure of cutting "THINGS" up into little pieces.

Unfortunately for MS folks they (MMP-9s) like to cut a hole in our BBB Blood Brain Barrier and then enter the brain and cut our myelin into three components that the other hungry characters like to dine on.

They (MMPs) all have a zinc ion tip that allows them to break down hydrogen bonds in tissue thus allows absorption of dead or dying tissue to be reabsorbed or sent via the lymph system to others places to exit out the poop shoot.

The MMP-9s usually have an accompanying regulator protein that is suppose to make sure that it only "eat/cuts up" BAD stuff. This is called a TIMP-1. For NORMAL folks there is a one-to-one ratio of MMP-9 to TIMP-1s.

Sad to say for us MS folks that we have lots of MMP-9s that I call ROGUE MMP-9s that have no accompanying regulating timp-1. Just before and during a MS relapse the total MMP-9s level rise significently(ALSO LOTS OF ROGUE MMP-9s). The first thing they do is cut a BIG hole in our BBB Blood Brain Barrier!! They then enter and do the following...

They just wander around the brain cutting up anything "active" and when they run into an active transmission cable the eat through it, The outside of that cable is called myelin. (a fatty insulating substance)

The advantage of taking an Interferon Beta is that after about 4 to 6 months of starting beta treatment that the ratio of MMP-s to TIMP-1s goes back to the desirable one-to-one ration.

There are NO effective drugs to lower just MMP-9s. Some drugs were developed but they shut them all (all 27) down and killed the host.

Some antibiotics seem to lower MMP-9s quite well but taking those for long periods of time can be equally deadly. Likewise taking some steroids can lower the MMP-9s quite well but can be equally deadly over the long haul.

I have many of the FULL TEXT articles in my Web Storage area but since I am unworthy to tell you how to get there to read them I will just say they are GREAT and have LOTS of neat pics and charts. I will post the short abstracts of them.

jackD

Hello Jack and welcome to NeuroTalk :)

I'm glad to see you posting. I have always appreciated your information.

If you have the time and wouldn't mind I would like to see you start a thread about supplements. I liked the information you provided at BT.

More MMP-9 & TIMP-1 comments

Here is a rather interesting exchange I had with Ed Hill related to this in Dec 2003.

Quote:

This is Ed Hill to me (jackD)

gonna pour a little skunked beer on this one...sorry.

jackD, you are absolutely right that modulation of MMP-9 in the CNS
helps us greatly.

and noodling TIMP (Tissue Inhibitors of MetalloProteinses) production
thereby correcting the TIMP/MMP imbalance long known to be common to
MSrs is a tempting target.

apologies to those already up on the following.

think MMP as open hand with zinc ion in the palm. the zinc ion when
exposed breaks down certain proteins by busting up weak hydrogen bonds
on contact.

TIMPs might best be seen as a second hand closing over the first,
fingers entwined so blocking contact between the zink ion and other
proteins.

normally, like most other MMPs 9 travels with it's TIMP in tow doing
no harm. there are a few ways to remove the TIMP and activate the
zinc ion. and in some cases, particularly in the MS CNS there aren't
enough TIMPs to go around.

MMP-9 has been shown to cut through the vessel walls of the BBB making
way for immune system elements to get in. and inside the CNS it does
all kinds of damage.

on the other hand...

MMP-9 is a working part of the extracellular matrix. that's the gooey
space between cells. when cells die or eject some garbage, MMP-9 is a
major factor in cutting the junk into nice littel bits and sending 'em
off to the lymphatics.(the "other" circulatory system) from whence
they are shuffled out the poopshoot.

this makes noodling with the matrixins a tad tricky at best. MMP-9 is
also the main cutting tool allowing mensus and ovulation. you didn't
think the eggs just pop up on their own did you? that's a whole
article in itself.

i've written here 'bout this in days of yore.

it might just be the reason for women being struck more frequently by autoimmunity.

their whole MMP regulatory system is flipped over and rebooted every
month. that's a risky biz in my book.

anyways...

oncologists have been fiddling with MMP-9 among others because they
facilitate tumor vascularization. arthritis aka rheumatologists have
also done some great work in this area.

the catch?

THE SIDE EFFECTS SUCK!!!!

it's kind of like shutting down garbage collections because the trucks
smell bad.

great fer a few days. but soon the garbage piles up and it's not very pretty.

regards
ed

MORE FORMAL STATEMENT OF THE SAME STUFF

Quote:

1: Neuroscientist 2002 Dec;8(6):586-95

Matrix metalloproteinases and neuroinflammation in multiple sclerosis.

Rosenberg GA.

Department of Neurology, University of New Mexico Health Sciences Center,
Albuquerque, New Mexico 87131, USA.

Matrix metalloproteinases (MMPs) are extracellular matrix remodeling neutral
proteases that are important in normal development, angiogenesis, wound repair,
and a wide range of pathological processes.Growing evidence supports a key role
of the MMPs in many neuroinflammatory conditions, including meningitis,
encephalitis, brain tumors, cerebral ischemia, Guillain-Barre, and multiple
sclerosis (MS).
The MMPs attack the basal lamina macromolecules that line the
blood vessels, opening the blood-brain barrier (BBB). They contribute to the
remodeling of the blood vessels that causes hyalinosis and gliosis, and they
attack myelin. During the acute inflammatory phase of MS, they are involved in
the injury to the blood vessels and may be important in the disruption of the
myelin sheath and axons. Normally under tight regulation, excessive proteolytic
activity is detected in the blood and cerebrospinal fluid in patients with acute
MS. Because they are induced in immunologic and nonimmunologic forms of
demyelination, they act as a final common pathway to exert a "bystander" effect.

Agents that block the action of the MMPs have been shown to reduce the damage to
the BBB and lead to symptomatic improvement in several animal models of
neuroinflammatory diseases, including experimental allergic encephalomyelitis.

Such agents may eventually be useful in the control of excessive proteolysis
that contributes to the pathology of MS and other neuroinflammatory conditions.

PMID: 12467380 [PubMed - in process]

: Semin Cell Dev Biol. 2008 Feb;19(1):42-51. Epub 2007 Jun 19.

MMPs in the central nervous system: where the good guys go bad.

Agrawal SM, Lau L, Yong VW.
Hotchkiss Brain Institute and the Department of Clinical Neuroscience, University of Calgary, Calgary, Alberta, Canada.

Matrix metalloproteinases (MMPs) are expressed in the developing, healthy adult and diseased CNS. We emphasize the regulation of neurogenesis and oligodendrogenesis by MMPs during CNS development, and highlight physiological roles of MMPs in the healthy adult CNS, such as in synaptic plasticity, learning and memory.

Nonetheless, MMPs as "the good guys" go bad in neurological conditions, likely aided by the sudden and massive upregulation of several MMP members.

We stress the necessity of drawing a fine balance in the treatment of neurological diseases, and we suggest that MMP inhibitors do have therapeutic potential early after CNS injury.

PMID: 17646116 [PubMed - indexed for MEDLINE]

i'm sorry you do not like our policies and guidlines jack. ones you agreed to when you joined.

we provide a forum, unlike many others where you don't see porn and other spam.

having to actually particapate with only 10 posts isn't much. it does keep people from joining just to post links.

Quote:

Originally Posted by Curious (Post 304394)

Thanks to ALL for saying hello and welcome. I know I will make the 10 post qualification however it did take me 2,756 posts on Braintalk before I was banned as jackD. I hope to make it to at least 3,000 here. I was reborn again as Braindead on Braintalk. I now have 338 posts as Braindead.

jackD AKA Braindead

Jack N Dalton

amn is over 5000, you should be safe. :D she does bribe the mods. :rolleyes:

heck..i'm over 9000 and doc still puts up with me. :p

Welcome to Neurotalk, Jack and, so far, I really do mean that. Don't expect us to be rude, as, they have always been, at that other place.

I remember your good posts, but, unfortunately, I remember some of your umm...not so good, posts, as well. Please treat us with the same respect you would expect for yourself, and all will be great.:)

I have always been interested in the MMP-9 theory, and finding something to counteract the damage it does. Have you found anything safe, we can add to our supplement regimine, that has helped to accomplish this noble feat?

Again, Welcome Friend and let us know if there is anything we can do to support you, in your fight against MS. We are even allowed to have some good clean fun, here......visit the Stumble Inn (cute huh?) and find out.:D

Quote:

Originally Posted by SallyC (Post 304713)

Sally

I am glad to be here and hope to contribute a lot of practical helpful info.

I have some VERY GOOD info on how to reduce/lower those nasty MMP-9s populations but must wait until I have 10 posts before posting it because I am trying to fool them into thinking I am a nice guy and I must show some pics and .pdf stuff on my web storage area and some links.

But you just wait until I get my 10 postings and the REAL JACK will appear!!!

jackD

jack, be sure you read the guidlines about posting articles. especially about copyright. we can't post full articles. just a few sentences and the link MUST be included.

we had some backlash from from some authors.

i fyou have any questions, please pm me. oh...and pm the links to the ones you posted. i don't want to have to pull them. the edit time may have expired for you to include them.

Thanks for all of the information. It is going to take me a while to read through it!

I have Optic Neuritis and 5 children to take care of. Not much time to read! But I do appreciate the help.

Quote:

Originally Posted by slskckjebw (Post 304882)

Thanks for all of the information. It is going to take me a while to read through it!

I have Optic Neuritis and 5 children to take care of. Not much time to read! But I do appreciate the help.

Yep! I started with a BIG ON attack and loss all color vision in my right eye. For me it was at age 52. This was a big suprise to both me and the Drs at Johns Hopkins. Men do not usually get MS at that age. The ON did get rid of all those darn RED traffic lights. I got to work much faster in those days. I had repeated ON attacks every winter Jan-Feb but started Avonex and lots of supplements like VIT D3, green tea extract, alpha lipoic acid etc etc and that cycle came to a halt.

Keep up the fight and you can overcome the other big MS problems like cognitive loss and excessive fatigue.

jackD

If you want to maximize Avonex (or any beta interferon), lowering MMP-9s will prevent it from being degraded by being cleaved into parts thus killing its Activity/Effectiveness.

http://www.cnsforum.com/commentedite...9/default.aspx

Also getting the most activity from the least amount of near natural (human) interferon like Avonex will usually result in MUCH LESS neutralizing antibody formation (2-5% vrs 20-26%).

Unfortunately for MS folks (MMP-9s) also like to cut a hole in our BBB Blood Brain Barrier and then enter the brain and cut our myelin into three components that the other hungry characters like to dine on. This mechanism of destruction caused by excessive agressive MMP-9s is a good target for reduction and should reduce MS damage if lowered a tad. Actual abstracts and one major study on my web page are provided below.

http://home.ix.netcom.com/~jdalton/Yongrev.pdf

SEE FIGURE 2 and MS info on page 505

Things that reduce MMP-9s (AKA gelatinase B)
This list of GOOD "things" for MS should seem familiar - This is WHY???

VIT D3 .................................REDUCES MMP-9s

RESVERATROL (Grape Skin Extract) ...REDUCES MMP-9s
(NOT GRAPE SEED EXTRACT)

GREEN TEA EXTRACT(EGCGs)... REDUCES MMP-9s

ALPHA LIPOIC ACID (R-lipoic/ R-Dihdro-LipoicAcid) ... REDUCES MMP-9s

NAC N-Acetyl-L-Cysteine .......REDUCES MMP-9s

STATIN DRUGS (i.e Zocor) .....REDUCES MMP-9s

Omega-3s (ie Fish oil) ...........REDUCES MMP-9s

Minocycline/Doxycycline.........REDUCES MMP-9s

Curcumin.............................REDUCES MMP-9s

Pycnogenol (Pine bark extract)..REDUCES MMP-9s

Chondroitin sulfate (CS) and CS plus glucosamine sulfate (GS) ..REDUCES MMP-9s

Interferon Betas 1a/1b...........REDUCES MMP-9

(of course Steroids ....REDUCES MMP-9s)

***NOTE*** ( gelatinase B = MMP-9) ***NOTE***

I have lots more information on this MMP - MS - INTERFERON-beta connection and will elaborate it if there is some interest in this subject here.

Jack n dalton - jackD

Quote:

Lancet Neurol. 2003 Dec;2(12):747-56.

Functional roles and therapeutic targeting of gelatinase B(MMP-9) and chemokines in
multiple sclerosis.

Opdenakker G, Nelissen I, Van Damme J.
GO, IN, and JVD are at the Rega Institute for Medical Research, University
of
Leuven, Belgium

Multiple sclerosis (MS) is a demyelinating disease of the CNS of unknown
cause. Pathogenetic mechanisms, such as chemotaxis, subsequent activation of
autoreactive lymphocytes, and skewing of the extracellular proteinase
balance, are targets for new therapies.

Matrix metalloproteinase gelatinase B (MMP-9) is upregulated in MS and was
recently shown to degrade interferon beta, one of the drugs used to treat
MS.

Consequently, the effect of endogenously produced interferon beta or
parenterally given interferon beta may be increased by gelatinase B(MMP-9)
inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and
inhibition of hydoxymethyl-glutaryl-coenzyme-A reductase to lower expression
of gelatinase B(MMP-9), may become effective treatments of MS, alone or in
combination with interferon beta. This may allow interferon beta to be used
at lower doses and prevent side-effects.

PMID: 14636780 [PubMed - in process]

1: Brain. 2003 Jun;126(Pt 6):1371-81.

Gelatinase B/matrix metalloproteinase-9(MMP-9) cleaves interferon-beta and is a
target for immunotherapy.

Nelissen I, Martens E, Van den Steen PE, Proost P, Ronsse I, Opdenakker G.
Rega Institute for Medical Research, Laboratory of Molecular Immunology,
University of Leuven, Leuven, Belgium.

Parenteral administration of interferon (IFN)-beta is one of the currently
approved therapies for multiple sclerosis. One characteristic of this
disease is the increased production of gelatinase B(MMP-9), also called matrix
metalloproteinase (MMP-9) Gelatinase B is capable of destroying the
blood-brain barrier, and of cleaving myelin basic protein into
immunodominant and encephalitogenic fragments, thus playing a functional
role and being a therapeutic target in multiple sclerosis. Here we
demonstrate that gelatinase B(MMP-9) proteolytically cleaves IFN-beta, kills its
activity, and hence counteracts this cytokine as an antiviral and
immunotherapeutic agent. This proteolysis is more pronounced with
IFN-beta-1b than with IFN-beta-1a. Furthermore, the tetracycline
minocycline, which has a known blocking effect in experimental autoimmune
encephalomyelitis, an in vivo model of acute inflammation in multiple
sclerosis, and other MMP inhibitors prevent the in vitro degradation of
IFN-beta by gelatinase B(MMP-9). These data provide a novel mechanism and rationale
for the inhibition of gelatinase B(MMP-9) in diseases in which IFN-beta has a
beneficial effect. The combination of gelatinase B(MMP-9) inhibitors with better
and lower pharmacological formulations of IFN-beta may reduce the
side-effects of treatment with IFN-beta, and is therefore proposed for
multiple sclerosis therapy and the immunotherapy of viral infections.

PMID: 12764058 [PubMed - indexed for MEDLINE]

1: J Neuroimmunol 2002 Oct;131(1-2):104-14

Alpha lipoic acid inhibits T cell migration into the spinal cord and
suppresses and treats experimental autoimmune encephalomyelitis.

Marracci GH, Jones RE, McKeon GP, Bourdette DN.
Department of Neurology, Oregon Health and Science University, Portland, OR
97201, USA.

Oxidative injury may be important to the pathogenesis of multiple sclerosis
(MS). We tested the antioxidant alpha lipoic acid (ALA) in an experimental
murine model of MS, experimental autoimmune encephalomyelitis (EAE). ALA was
administered to SJL mice 7 days after immunization with proteolipid protein
(PLP) 139-151 peptide. Mice that received 5-100 mg/kg/day of ALA had
dose-dependent reductions in their 10-Day Cumulative Disease Scores (10-Day
CDS) by 23-100%. Minimal inflammation, demyelination and axonal loss
occurred in the spinal cords (SC) of ALA-suppressed mice, and there was a
marked reduction in CD3+ T cells and CD11b+ monocyte/macrophage cells within
the SC. Mice treated with ALA (100 mg/kg/day) commencing on the first day of
clinical EAE had a significant reduction in 10-Day CDS. SC of ALA-treated
mice had reduced demyelination and axonal loss and a rapid reduction in CD3+
T cells. In vitro, ALA and its reduced form, dihydrolipoic acid, inhibited
the activity of matrix metalloproteinase-9 (MMP-9) in a dose-dependent
fashion. ALA is highly effective at suppressing and treating EAE and does so
by inhibiting T cell trafficking into the SC, perhaps by acting as a matrix
metalloproteinase inhibitor.

PMID: 12458042 [PubMed - indexed for MEDLINE]

1: Neurology 2002 Oct 8;59(7):990-7
Comment in:
Neurology. 2002 Oct 8;59(7):970-1.

Statins as immunomodulators: comparison with interferon-beta 1b in MS.

Neuhaus O, Strasser-Fuchs S, Fazekas F, Kieseier BC, Niederwieser G, Hartung
HP, Archelos JJ.
Department of Neurology, Multiple Sclerosis Research Group,
Karl-Franzens-Universitat, Graz, Austria.
BACKGROUND: Recent data suggest that statins may be potent immunomodulatory
agents. In order to evaluate the potential role of statins as
immunomodulators in MS, the authors studied their immunologic effects in
vitro and compared them to interferon (IFN)beta-1b. METHODS: Peripheral
blood mononuclear cells (PBMC) obtained from untreated or IFN beta-1-treated
patients with relapsing-remitting MS or from healthy donors (HD) and T cells
were stimulated with concanavalin A, phytohemagglutinin, or antibody to CD3
in the presence of lovastatin, simvastatin, mevastatin, IFN beta-1b, or
statins plus IFN beta-1b. The authors analyzed proliferative activity of T
cells and B cells, cytokine production and release, activity of matrix
metalloproteinases (MMP), and surface expression of activation markers,
adhesion molecules, and chemokine receptors on both T and B cells. RESULTS:
All three statins inhibited proliferation of stimulated PBMC in a
dose-dependent manner, with simvastatin being the most potent, followed by
lovastatin and mevastatin. IFN beta-1b showed a similar effect; statins and
IFN beta-1b together added their inhibitory potentials. Furthermore, statins
reduced the expression of activation-induced adhesion molecules on T cells,
modified the T helper 1/T helper 2 cytokine balance, reduced MMP-9, and
downregulated chemokine receptors on both B and T cells. Besides strong
anti-inflammatory properties, statins also exhibited some proinflammatory
effects. CONCLUSIONS:
Statins are effective immunomodulators in vitro that merit evaluation as
treatment for MS.

PMID: 12370451 [PubMed - indexed for MEDLINE]

1: QJM 2002 Dec;95(12):787-796

Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR
genotype: mechanisms for inflammatory damage in chronic disorders?
Timms PM, Mannan N, Hitman GA, Noonan K, Mills PG, Syndercombe-Court D,
Aganna E, Price CP, Boucher(2) BJ.
Departments of. Clinical Biochemistry, Diabetes and Metabolic Medicine and.
Haematology, Barts and The London, Queen Mary's School of Medicine and
Dentistry, University of London and. Department of Cardiology, 'Barts and
The London' NHS Trust, London, UK.

BACKGROUND:Vitamin-D deficiency and vitamin-D receptor genotype (VDR) are
risk factors for several disorders with inflammatory components, including
coronary heart disease (CHD) and diabetes, though the mechanisms involved
are unclear. Aim: To examine the hypothesis that vitamin D status modulates
the matrix metalloproteinase (MMP) system in a population with a high
prevalence of vitamin D deficiency, a situation affecting susceptibility to
CHD and diabetes.

DESIGN:
Prospective cross-sectional, interventional and embedded studies. METHODS:
Circulating MMP2,9, the inhibitor TIMP-1 and C-reactive protein (CRP) were
measured during studies of vitamin-D deficiency as a risk factor for type 2
diabetes and CHD in 171 healthy British Bangladeshi adults, free of known
diabetes or major illness. Vitamin D status, VDR genotype, body-build, blood
pressure, lipid and insulin profiles, glucose tolerance, fibrinogen, PAI-1,
folate and homocysteine were measured. Vitamin-D-deficient subjects were
re-assessed after 1 years' supplementation. MMP, TIMP-1 and CRP levels were
measured in 41 subjects halfway through 5-year follow-up. Independent
determinants of circulating concentrations of MMP9, TIMP-1 and CRP were
assessed by multiple regression analysis.

RESULTS: Vitamin D status was the sole determinant of circulating MMP9
(inversely) and an independent determinant of CRP (inversely). Determinants
of TIMP-1 were MMP9, systolic blood-pressure (directly) and VDR genotype
(TaqI). Significant reductions in MMP9 (-68%), TIMP-1 (-38%) and CRP (-23%)
concentrations followed vitamin-D supplementation. DISCUSSION: Vitamin-D
insufficiency is associated with increased circulating MMP2,9 and CRP,
correctable by supplementation. This finding provides a possible mechanism
for tissue damage in chronic inflammatory conditions, including CHD and
diabetes.

PMID: 12454321 [PubMed - as supplied by publisher]

1: Acta Pharmacol Sin. 2003 Nov;24(11):1167-71.

Resveratrol inhibits matrix metalloproteinase-9 transcription in U937 cells.

Li YT, Shen F, Liu BH, Cheng GF.

Department of Pharmacology, Institute of Materia Medica, Chinese Academy of
Medical Sciences and Peking Union Medical College, Beijing 100050, China.

AIM: To examine the inhibitory effect of resveratrol on matrix
metalloroteinase-9 (MMP-9) and explore its mechanism. METHODS: MMP-9
activity was analyzed by gelatin zymography; MMP-9 protein was detected by Western
blot; MMP-9 mRNA expression was investigated by RT-PCR. Activation of activator
protein -1 (AP-1) was measured by electrophoretic mobility shift assay
(EMSA).

RESULTS: MMP-9 activity in U937 cells increased significantly after exposed
to PMA at 10 nmol/L for 24 h without FCS (P<0.01). Resveratrol at 1 and 10
micromol/L showed significant inhibition on MMP-9 activity (P<0.05 and
P<0.01, respectively). Western blot and RT-PCR experiments displayed that MMP-9
protein (P<0.01) and mRNA expression (P<0.01) increased significantly in PMA-treated
U937 cells. Resveratrol at 1 and 10 micromol/L showed inhibitory effects on
MMP-9 protein production and MMP-9 mRNA expression (P<0.05). The activation
of AP-1 induced by PMA was also extensively inhibited by resveratrol at 0.1, 1,and
10 micromol/L. CONCLUSION: The inhibitory effect of resveratrol on MMP-9
activity may be partly through suppression of activation of nuclear
transcription factor AP-1, and inhibition of MMP-9 mRNA expression and MMP-9
protein production.

PMID: 14627504 [PubMed - in process]

Since lots of MS folks think that taking "Grape Seed Extract" is good and I have posted the opposite I will provide my reason for having my opinion.

IF and ONLY if we accept that increasing GAMMA INTERFERON is BAD for MS folks will my argument prove sound.

I would hope that everyone can accept this as a fact.

Some Gamma Interferon at low levels is necessary for good health and myelin repair.

The medical literature shows that ADDING/INCREASING Gamma Interferon has worsened MS folks in clinical studies.

jackD

Quote:

Clin Diagn Lab Immunol 2002 Mar;9(2):470-6

Grape seed extract activates Th1 cells in vitro.

Nair N, Mahajan S, Chawda R, Kandaswami C, Shanahan TC, Schwartz SA.

Division of Allergy, Immunology, and Rheumatology, Department of Medicine, State University of New York at Buffalo and Kaleida Health, 14203, USA.

Although flavonoids manifest a diverse range of biological activities, including antitumor and antiviral effects, the molecular mechanisms underlying these activities await elucidation. We hypothesize that the flavonoid constituents of a proprietary grape seed extract (GSE) that contains procyandins exert significant antiviral and antitumor effects, by inducing production of the Th1-derived cytokine gamma interferon (IFN-gamma) by peripheral blood mononuclear cells) from healthy donors. Our results show that GSE significantly induced the transcription of IFN-gamma mRNA as demonstrated by reverse transcription-PCR but had no effect on the Th2-derived cytokine interleukin-6. The enhancing effect of GSE on IFN-gamma expression was further supported by a concomitant increase in the number of cells with intracytoplasmic IFN-gamma as well as the synthesis and secretion of IFN-gamma.

Our results demonstrate that the potentially beneficial immunostimulatory effects of GSE may be mediated through the induction of IFN-gamma.

PMID: 11874895 [PubMed - indexed for MEDLINE

MMP Arthritis connection

This thread is a bit of a mess.. so I will get off the main track without fear of destroying the beauty of this messy thread.

This study from Lebanon shows that MMPs do the actual damage in BOTH rheumatoid arthritis (RA) and osteoarthritis (OA).

I have found that my MMP reduction program of supplements has done wonders at reducing mr OA arthritis. I have had both kneees operated on and things were still so bad I walked around my house on crutches.

My finger joints were red and swollen and VERY VERY SORE.

MY thumb was almost useless because of the pain generated at the base of the thumb when I used my right hand.

Since I started my MMP-9 reduction program I have had NO pain for the last 6 yes!!! Yes - no more crutches, no red finger joints, no more annual shots in the knees!!

You must also reduce interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and maybe IL-12 also. That is no BIG deal because some of the MMP-9 reduction "thingies" does this also quite well.

jackD

P.S. For more info go to PubMed and search on "MMP arthritis".

P.P.S. - It is real shame that this Medical folks cannot find ways to reduce these nasty MMPs. I had no problem and have discovered two more "thingies" that reduce MMP-9s in the las two weeks. I will post them later after more research.

http://www.ncbi.nlm.nih.gov/pubmed/1...?dopt=Abstract

Quote:

Front Biosci. 2006 Jan 1;11:529-43.

Matrix metalloproteinases: role in arthritis.

Burrage PS, Mix KS, Brinckerhoff CE.

Department of Biochemistry, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, Lebanon, NH 03756, USA.

The irreversible destruction of the cartilage, tendon, and bone that comprise synovial joints is the hallmark of both rheumatoid arthritis (RA) and osteoarthritis (OA). While cartilage is made up of proteoglycans and type II collagen, tendon and bone are composed primarily of type I collagen. RA is an autoimmune disease afflicting numerous joints throughout the body; in contrast, OA develops in a small number of joints, usually resulting from chronic overuse or injury.

In both diseases, inflammatory cytokines such as interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF-alpha) stimulate the production of matrix metalloproteinases (MMPs), enzymes that can degrade all components of the extracellular matrix.

The collagenases, MMP-1 and MMP-13, have predominant roles in RA and OA because they are rate limiting in the process of collagen degradation. MMP-1 is produced primarily by the synovial cells that line the joints, and MMP-13 is a product of the chondrocytes that reside in the cartilage.

In addition to collagen, MMP-13 also degrades the proteoglycan molecule, aggrecan, giving it a dual role in matrix destruction.

:eek:Expression of other MMPs such as MMP-2, MMP-3 and MMP-9, is also elevated in arthritis and these enzymes degrade non-collagen matrix components of the joints.

Significant effort has been expended in attempts to design effective inhibitors of MMP activity and/or synthesis with the goal of curbing connective tissues destruction within the joints.

:rolleyes:To date, however, no effective clinical inhibitors exist. Increasing our knowledge of the crystal structures of these enzymes and of the signal transduction pathways and molecular mechanisms that control MMP gene expression may provide new opportunities for the development of therapeutics to prevent the joint destruction seen in arthritis.

PMID: 16146751 [PubMed - indexed for MEDLINE]

http://groups.google.com/group/alt.s...3d3011b530e3b6

At least they are still trying.

jackD

Quote:

: Curr Med Chem. 2008;15(14):1388-95.

Progress in the development of matrix metalloproteinase inhibitors.

Tu G, Xu W, Huang H, Li S.

Department of Medicinal Chemistry, School of Pharmaceutical Sciences, ShanDong University, 44, West Culture Road, Ji'nan, 250012, P.R. China. xuwenf@sdu.edu.cn.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodeling of extracellular matrix proteins that are associated with the tumorigenic process. MMPs promote tumor invasion and metastasis, regulating host defense mechanisms and normal cell function.

Thus, MMP inhibitors (MMPIs) are expected to be useful for the treatment of diseases such as cancer, osteoarthritis, and rheumatoid arthritis.

A vast number of MMPIs have been developed in recent years.

:eek:With the failure of these inhibitors in clinical trials, more efforts have been directed to the design of specific inhibitors with different Zn-binding groups.

This review summarizes the current status of MMPIs, the design of small molecular weight MMPIs , a brief description of available three-dimensional MMP structures, a review of the proposed therapeutic utility of MMPIs, and a clinical update of compounds that have entered clinical trials in humans.

PMID: 18537616 [PubMed - in process]