Maximizing INTERFERON-Beta effectiveness

A board to discuss the Multiple Sclerosis modifying drug Avonex
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Maximizing INTERFERON-Beta effectiveness

Post by jackD » Mon Jul 02, 2007 6:32 pm

MMP-9s KILL the activity of ALL IFN-Betas.

It is a VERY GOOD IDEA to lower MMP-9s if taking an Ifn-Beta drug.

:wink: 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.

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%).

Clin Ther. 2007 Sep;29(9):2031-48.

Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis.

Schwid SR, Panitch HS.SourceDepartment of Nuerology, University of Rochester, Rochester, New York 14642, USA.

BACKGROUND: Interferon (IFN)-beta therapy represents an important advance in the management of relapsing multiple sclerosis (MS), but information about the relative benefits and risks of available preparations is limited.

OBJECTIVE: This report describes the full results of the Evidence of Interferon Dose-response-European North American Comparative Efficacy (EVIDENCE) study, combining analyses that were previously reported in separate publications for different phases of the study.

METHODS: The EVIDENCE study was a multicenter, randomized, assessor-blinded comparison of 2 IFN-beta dosing regimens. In the study, patients with relapsing MS were randomly assigned to SC IFN-beta1a 44 lag TIW (Rebif, Serono Inc., Geneva, Switzerland) or IM IFN-betala 30 mug QW (Avonex, Biogen Idec, Cambridge, Massachusetts) for 1 to 2 years. The primary clinical end point during the comparative phase was the proportion of patients who remained free from relapses; secondary and tertiary clinical end points included the annualized relapse rate and time to first relapse, re- spectively. All clinical and magnetic resonance imaging (MRI) evaluations were performed by blinded assessors. In the crossover phase of the study, patients who were originally randomized to low-dose QW treatment switched to the high-dose TIW treatment for an additional 8 months. Adverse events were determined by spontaneous reporting and monthly laboratory testing during the comparative phase.

RESULTS: A total of 677 patients were enrolled in the study and evenly randomized to treatment; 605 patients completed the comparative phase and 439 completed the crossover phase. During the comparative phase, a significantly higher proportion of patients in the high-dose TIW treatment group remained free from relapses when compared with patients in the low-dose QW treatment group (adjusted odds ratio, 1.5; 95% CI, 1.1-2.0; P = 0.023). The high-dose TIW regimen was also associated with a significant reduction in the annualized relapse rate (-17%; P = 0.033) and a prolonged time to first relapse (hazard ratio, 0.70; P = 0.002). MRI measures of disease activity were significantly reduced in the high-dose TIW group compared with the low-dose QW treatment. During the crossover phase, a 50% reduction in mean relapse rates was observed in patients who converted from low-dose QW treatment to high-dose TIW treatment (P < 0.001), with significant concomitant reductions in MRI activity. Injection-site reactions were significantly more common with high-dose TIW treatment than with low-dose QW treatment (85% vs 33%; P < 0.001). Neutralizing antibody formation was more common with high-dose TIW treatment than with low-dose QW treatment (26% vs 3%; P < 0.001).

CONCLUSIONS: The comparative phase of the EVIDENCE study found that treatment of MS with SC IFN-beta1a 44 microg TIW was associated with a significant reduction in clinical and imaging measures of disease activity over 1 to 2 years, when compared with IM IFN-betala 30 microg QW treatment. The crossover phase found that patients who changed from low-dose QW treatment to high-dose TIW treatment experienced enhanced benefits of treatment without a substantial increase in adverse events.

PMID:18035202[PubMed - indexed for MEDLINE]

Things that reduce MMP-9s (AKA gelatinase B)

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

QUERCETIN..........................REDUCES MMP-9s

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

RESVERATROL (Grape Skin Extract) ...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-9s

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

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. For the real techie stuff check the link shown below
(see fig 2 and narrative on page 505)
THE NERVOUS SYSTEM ... inases.pdf

Matrix metalloproteinases and their multiple roles in
neurodegenerative diseases


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

Functional roles and therapeutic targeting of gelatinase B 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
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

Consequently, the effect of endogenously produced interferon beta or
parenterally given interferon beta may be increased by gelatinase B
inhibitors. Blockage of chemotaxis or cell adhesion molecule engagement, and
inhibition of hydoxymethyl-glutaryl-coenzyme-A reductase to lower expression
of gelatinase B, 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 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, 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 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. These data provide a novel mechanism and rationale
for the inhibition of gelatinase B in diseases in which IFN-beta has a
beneficial effect. The combination of gelatinase B 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: 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.

PMID: 12467380 [PubMed - in process]
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Post by dignan » Mon Jul 02, 2007 8:30 pm

jackD? THE jackD?! Of Braintalk fame? I think I'd recognize your unique posting style anywhere. Welcome to ThisIsMS. I don't know for sure, but I think you might like it here...

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Post by jackD » Mon Jul 02, 2007 8:50 pm

Thanks for the welcome.

I posted all this stuff before in 2000-2001-2002 before in before all the great validating studies were published. I seem to be alone in the lowering MMP-9 approach. It is a bit strange that the rest of the MS world in some other discussion groups are in such a "Pity Party" mood and cannot see how simple it is to help the Avonex and other IFN-Betas work better.

Taking lots of VIT D3(4,000-5,000 ius) and lowering MMP-9s and capping TNF-a, IL-12, IL-1beta and Gamma Interferon will really maximize the effectiveness of the IFN-Beta and allow it to do its work.

The disappointing fact about Avonex and other IFN-Betas is that they are ineffective during relapses because of the high MMP-9 levels and they take about 6 months before the full effects show up. Long term Avonex seems to be the best. I took it for 10 years and I am doing OK. ... CES+MMP-9s

jackD - Braindead AKA Jack N Dalton
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Post by Lainie » Sun Jul 08, 2007 5:24 pm

Apologies if this is a stupid question.

I thought that ECGC (in green tea) actually enhanced immune function, and so was not a good idea for those trying to suppress their immune system. I stopped drinking green tea when I started Avonex. Is green tea actually a good idea when on Avonex, based on what you are saying?

Thanks for a great post!

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Green Tea & MMP-9s Multiple Sclerosis

Post by jackD » Sun Jul 08, 2007 9:44 pm

Green Tea & MMP-9s

Green Tea is a winner!!

HOWEVER Drinking a cup or two WILL NOT HELP MUCH!!!~

Get some MEGA GREEN TEA EXTRACT from LEF.ORG and take two a day.

I still have a large pot of Green & White tea tea each day.

Lainie You should re-read my first post again and check the links.

MMP-9s KILL Interferon Betas (AVONEX). Cleaves it into little pieces, makes it inert. I thought I made that point.

MMP-9s cut hole in BBB (Blood Brain Barrier) and then proceed to cut myelin into three components that other immune players love to dine on.

That is why reducing them is such a good idea.

Green Tea is protective in many ways without actually enhancing the immune function. It fights Cancer,inflammation and lowers MMP-9s levels. MMP-9s also make some nasty versions of TNF-a.

Some VERY VERY simple supplements can do the job quite well with almost no side effects. I do not take MEGA doses of any of them except green tea. I also take four different kinds/brands of RESVERATROL plus a glass and a half of some Great red wine each day.


J Immunol. 2004 Nov 1;173(9):5794-800.

Green tea epigallocatechin-3-gallate mediates T cellular NF-kappa B inhibition and exerts neuroprotection in autoimmune encephalomyelitis.

Aktas O, Prozorovski T, Smorodchenko A, Savaskan NE, Lauster R, Kloetzel PM, Infante-Duarte C, Brocke S, Zipp F.

Institute of Neuroimmunology, Neuroscience Research Center, Charité, Berlin, Germany.

Recent studies in multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), point to the fact that even in the early phase of inflammation, neuronal pathology plays a pivotal role in the sustained disability of affected individuals.

:) We show that the major green tea constituent, (-)-epigallocatechin-3-gallate (EGCG), dramatically suppresses EAE induced by proteolipid protein 139-151.

:) EGCG reduced clinical severity when given at initiation or after the onset of EAE by both limiting brain inflammation and reducing neuronal damage. In orally treated mice, we found abrogated proliferation and TNF-alpha production of encephalitogenic T cells. In human myelin-specific CD4+ T cells, cell cycle arrest was induced, down-regulating the cyclin-dependent kinase 4. Interference with both T cell growth and effector function was mediated by blockade of the catalytic activities of the 20S/26S proteasome complex, resulting in intracellular accumulation of IkappaB-alpha and subsequent inhibition of NF-kappaB activation. Because its structure implicates additional antioxidative properties, :) EGCG was capable of protecting against neuronal injury in living brain tissue induced by N-methyl-D-aspartate or TRAIL and of directly blocking the formation of neurotoxic reactive oxygen species in neurons. Thus, a natural green tea constituent may open up a new therapeutic avenue for young disabled adults with inflammatory brain disease by combining, on one hand, anti-inflammatory and, on the other hand, neuroprotective capacities.

PMID: 15494532 [PubMed - indexed for MEDLINE]


1: Biochim Biophys Acta. 2000 Mar 16;1478(1):51-60.

Matrix metalloproteinase inhibition by green tea catechins.

Demeule M, Brossard M, Page M, Gingras D, Beliveau R.

Laboratoire de Medecine Moleculaire, Hopital Sainte-Justine - UQAM, C.P. 8888,
Succursale centre-ville, Montreal, QC, Canada.

We have investigated the effects of different biologically active components from natural products, including green tea polyphenols (GTP), resveratrol, genistein and organosulfur compounds from garlic, on matrix metalloproteinase (MMP)-2, MMP-9 and MMP-12 activities. GTP caused the strongest inhibition of the three enzymes, as measured by fluorescence assays using gelatin or elastin as substrates. The inhibition of MMP-2 and MMP-9 caused by GTP was confirmed by
gelatin zymography and was observed for MMPs associated with both various rat tissues and human brain tumors (glioblastoma and pituitary tumors). The activities of MMPs were also measured in the presence of various catechins isolated from green tea including (-)-epigallocatechin gallate (EGCG), (-)-epicatechin gallate(ECG), (-)-epigallocatechin (EGC), (-)-epicatechin (EC) and (+)-catechin (C). :D The most potent inhibitors of these activities, as measured by fluorescence and by gelatin or casein zymography, were EGCG and ECG. GTP and the different catechins had no effect on pancreatic elastase, suggesting that the effects of these molecules on MMP activities are specific.

Furthermore, in vitro activation of proMMP-2 secreted from the glioblastomas cell line U-87 by the lectin concanavalin A was completely inhibited by GTP and specifically by EGCG. These results indicate that catechins from green tea inhibit MMP activities and proMMP-2 activation.

PMID: 10719174 [PubMed - indexed for MEDLINE]
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Post by jackD » Sun Jul 08, 2007 11:56 pm

L-Theanine is contained in Green Tea and I add an extra 200 mg of it to my Great Tea/White Pot each day.


Theanine is an amino acid found in green tea that produces
tranquilizing effects in the brain. In Japan, soft drinks and
chewing gum are spiked with theanine for the purpose of
inducing relaxation.

Although theanine creates a feeling of
relaxation, it doesn't shut down the brain. Studies on rodents
show that theanine enhances the ability to learn and remember.
By shutting off worry central, theanine appears to increase
concentration and focus thought.

Theanine is different than kava-kava in that it doesn't cause
drowsiness, just relaxation. Theanine increases GABA, while
caffeine decreases it. GABA doesn't just relax, it also
creates a sense of well-being. Theanine's ability to increase
this brain chemical can literally put you in a better mood.
Theanine also increases levels of dopamine, another brain
chemical with mood-enhancing effects.

Protecting neurons
In studies on neurons in cell culture, theanine significantly
reverses glutamate-induced toxicity. In vivo studies show the
same effect in rodents. Glutamate-induced neuro-toxicity is a
major cause of degenerative brain disease.

Many Americans suffer from slightly elevated blood pressure,
but don't know they have it. Chronic high blood pressure
inflicts damage on the delicate cerebral vascular network and
increases the risk of stroke. Theanine has been shown to help
lower blood pressure.

Theanine readily crosses the blood-brain barrier and changes
brain chemistry in a way that has been compared to
aromatherapy. Studies show that theanine is a non-toxic,
highly desirable mood modulator that can be enjoyed by
everyone except babies.

1: Biol Pharm Bull. 2002 Dec;25(12):1513-8.

Neuroprotective effects of the green tea components theanine and catechins.

Kakuda T.

Central Research Institute, Itoen, Ltd, Shuzuoka, Japan.

The neuroprotective effects of theanine and catechins contained in green tea are discussed. Although the death of cultured rat cortical neurons was induced by the application of glutamic acid, this neuronal death was suppressed with exposure to theanine. The death of hippocampal CA1 pyramidal neurons caused by transient forebrain ischemia in the gerbil was inhibited with the ventricular preadministration of theanine. The neuronal death of the hippocampal CA3 region by kainate was also prevented by the administration of theanine. Theanine has a higher binding capacity for the AMPA/kainate receptors than for NMDA receptors,
although the binding capacity in all cases is markedly less than that of
glutamic acid.

The results of the present study suggest that the mechanism of the neuroprotective effect of theanine is related not only to the glutamate
receptor but also to other mechanisms such as the glutamate transporter,
although further studies are needed. One of the onset mechanisms for
arteriosclerosis, a major factor in ischemic cerebrovascular disease, is
probably the oxidative alteration of low-density lipoprotein (LDL) by active
oxygen species. The oxidative alterations of LDL were shown to be prevented by tea catechins. Scavenging of *O(2)(-) was also exhibited by tea catechins.

The neuroprotective effects of theanine and catechins contained in green tea are a focus of considerable attention, and further studies are warranted.

PMID: 12499631 [PubMed - indexed for MEDLINE]
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Editorial Neurology Journal

Post by jackD » Fri Jan 08, 2010 5:55 pm

My doctor(Christopher T. Bever) seems to agree with me and has stated his opinion in this editorial in the Neurology Journal. Some MMPs do GOOD things necessary for myelin repair. Excessive MMP-9s seem to do far more BAD things then GOOD.
. ... mmp-ms.doc

Matrix metalloproteinases in multiple sclerosis
Targets of therapy or markers of injury?

Christopher T. Bever, Jr., MD and Gary A. Rosenberg, MD

From the Neurology and Research Services, VA Maryland Health Care System, and the Departments of Neurology and Pharmacology and Experimental Therapeutics (Dr. Bever), School of Medicine, University of Maryland, Baltimore, MD; and Departments of Neurology, Neuroscience, and Cell Biology and Physiology (Dr. Rosenberg), University of New Mexico School of Medicine, Albuquerque, NM.

Address correspondence and reprint requests to Dr. Christopher Bever, Maryland Center for Multiple Sclerosis, 22 S. Greene St., N4W49, Baltimore, MD 21201.

Interferon-beta (IFNß) treatment represents a major advance in the management of MS that was made without a complete understanding of the cause of MS or the mechanism of action of IFNß. It is widely believed that MS is an immune-mediated disease and that the mechanism of action of IFNß is related to its immunomodulatory activity. In December 1996, two articles1,2 and an editorial3 were published that proposed, based on in vitro studies, that the therapeutic effect of IFNß in MS might be caused by an inhibition of matrix metalloproteinase-9 (92-kDa type IV collagenase or MMP-9). Transmigration of activated lymphocytes across basement membranes is dependent on secreted MMP-9, and the two studies showed that IFNß decreased MMP-9 secretion and lymphocyte transmigration across an artificial basement membrane. It was proposed that IFNß treatment blocked lesion formation in MS by limiting the entry of lymphocytes into the CNS. If this hypothesis is true, then lymphocytic-secreted MMP-9 activity should increase before the appearance of new lesions and secreted MMP-9 activity should decrease during treatment with IFNß in MS patients. This issue of Neurology contains two articles examining these questions in patients with MS, specifically following serum levels of MMP-9. Both provide data that support the hypothesis. Waubant et al.4 examined serum levels of MMP-9 and its inhibitor, tissue inhibitor to metalloproteinase-1 (TIMP-1), in patients with MS in a natural history study of patients undergoing monthly gadolinium-enhanced brain MRI scans. They found that MMP-9 levels increased without significant change in TIMP-1 immediately before the appearance of new gadolinium-enhancing MRI lesions. The second article, by Trojano et al.,5 examined changes in serum MMP-9 levels in patients during treatment with IFNß-1b. They found a decrease during the first year of treatment, which correlated with clinical and MRI evidence of therapeutic effect. Soluble intercellular adhesion molecule levels that correlate inversely with lymphocyte trafficking were also measured and were low before treatment but increased during treatment. Serum levels of MMP-2 (72-kDa type IV collagenase), which is normally present in brain and which may correlate with injury, were also measured and did not change. These results suggest that serum MMP-9 levels reflect blood–brain barrier (BBB) damage in patients with MS but do not clarify whether they are causing the damage. The results are consistent with the hypothesis that MMP-9 from lymphocytes is required for migration across the BBB and that IFNß inhibits MMP-9, blocking lesion formation. Because the cellular origins of MMP-9 were not determined and there were no direct measures of lymphocyte trafficking across the BBB in either study, other interpretations are possible. This hypothesis will be more directly tested in the near future when inhibitors of MMP-9 are tested in therapeutic trials in MS patients.

MMPs and TIMPs are present in brain and their levels change in other pathologic conditions.6 Even if MMPs do not prove to be a useful therapeutic target,7 determination of serum levels may prove to be a valuable marker of disease activity and treatment response in MS. Brain cells as well as circulating white blood cells make MMPs. Both MMP-2 and MMP-9 open the BBB by hydrolysis of type IV collagen, fibronectin, and laminin in the basal lamina. MMP-2 is normally present in brain and CSF, whereas MMP-9 is induced during inflammation and is under the control of the activator protein–1 (AP-1) and nuclear factor-kappa-ß sites in the promoter region of the gene. Astrocytes make MMP-2 normally and express MMP-9 during inflammatory stimulation. Microglia primarily produce MMP-9, and endothelial cells also express MMP-9. Cytokines stimulate the secretion of MMPs. Intracerebral injection of tumor necrosis factor- induces MMP-9 with peak levels occurring after 24 hours coincident with peak BBB damage.8 Intracerebral injection of MMP-2 opens the BBB, and TIMP-2 reverses the injury.9 A synthetic MMP inhibitor blocks BBB injury in experimental allergic encephalomyelitis. Studies in humans support those in experimental animals. MMP-9 is elevated in the CSF of patients with MS10 particularly during MS exacerbation and is dramatically lowered by high-dose corticosteroid treatment.11 Corticosteroids regulate MMP-9 in vitro by blocking the AP-1 transcription site. The two studies in this issue showing elevation of serum MMP-9 before the appearance of new gadolinium-enhancing MRI lesions4 and a reduction with IFNß treatment5 take this work an important step further. They offer the possibility of a serum marker of BBB opening and tissue injury in patients with MS. Although the serum changes appeared before MRI changes, simultaneous activation of the MMPs in the brain may have facilitated the breakdown of the BBB, which required more time to be seen by MRI. Further studies confirming these results and determining their relationship to changes in the brain will clarify the clinical utility of serum MMP-9 levels in monitoring MS disease activity and responses to treatment.

MMPs and their inhibitors have been studied extensively in inflammation, which may provide insight into the pathophysiology of the relapsing-remitting and chronic progressive subtypes of MS. Tissue MMP activity reflects a balance between MMPs and TIMPs. In acute inflammation, extracellular MMP activity is responsive to cytokines, leading to proteolysis of extracellular matrix and basement membranes. TIMPs are produced to restore normal MMP balance as part of the repair process. However, inhibition of MMPs will lead to extracellular matrix deposition. In chronic inflammatory states in other tissues, excessive TIMP production is associated with fibrosis and thickened blood vessels.12 In the brain, acute inflammation generally results in a cytokine-driven increase in MMP-9. Repair in tissues occurs through a shift to MMP-2 and TIMP secretion under the control of growth factors, such as transforming growth factor-ß. We hypothesize that, early in MS lesion development, increases in MMP-9 predominate with subsequent BBB damage. Later, as a lesion matures and repair processes take over, TIMPs and MMP-2 participate in the remodeling of extracellular matrix, which may correspond with the chronic progressive stage of MS. Changes in tissue MMPs and TIMPs may be reflected in serum and CSF, providing a useful window on this process. Further study is now needed to define long-term changes in serum MMPs and TIMPs and to determine whether changes correlate with disease subtype and responses to treatment throughout the course of MS.

1. Leppert D, Waubant E, Burk MR, Oksenberg JR, Hauser SL. Interferon beta-1b inhibits gelatinase secretion and in vitro migration of human T cells: a possible mechanism for treatment efficacy in multiple sclerosis. Ann Neurol 1996;40:846–852.[Medline]
2. Stuve O, Dooley NP, Uhm JH, et al. Interferon beta-1b decreases the migration of T lymphocytes in vitro: effects on matrix metalloproteinase-9. Ann Neurol 1996;40:853–863.[Medline]
3. Hartung H-P, Kieseier BC. Targets for the therapeutic action of interferon-beta in multiple sclerosis. Ann Neurol 1996;40:825–826.[Medline]
4. Waubant E, Goodkin DE, Gee L, et al. Serum MMP-9 and TIMP-1 levels are related to MRI activity in relapsing multiple sclerosis. Neurology 1999;53:1397–1401.[Abstract/Free Full Text]
5. Trojano M, Avolio C, Liuzzi GM, et al. Changes of serum ICAM-1 and MMP-9 induced by rIFNß-1b treatment in relapsing-remitting MS. Neurology 1999;53:1402–1408.[Abstract/Free Full Text]
6. Lukes A, Mun-Bryce S, Lukes M, Rosenberg GA. Extracellular matrix degradation by metalloproteinases and central nervous system diseases. Mol Neurobiol 1999;19:255–272.[Medline]
7. Kieseier BC, Seifert T, Giovannoni G, Hartung H-P. Matrix metalloproteinases in inflammatory demyelination: targets for treatment. Neurology 1999;53:20–25.[Abstract/Free Full Text]
8. Rosenberg GA, Estrada EY, Dencoff JE, Stetler-Stevenson WG. TNF- -induced gelatinase ß causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res 1995;703:151–155.[Medline]
9. Rosenberg GA, Kornfeld M, Estrada E, Kelley RO, Liotta LA, Stetler-Stevenson WG. TIMP-2 reduces proteolytic opening of blood-brain barrier by type IV collagenase. Brain Res 1992;576:203–207.[Medline]
10. Gijbels K, Masure L, Carton H, Opdenakker G. Gelatinase in the cerebrospinal fluid of patients with multiple sclerosis and other inflammatory neurological diseases. J Neuroimmunol 1992;41:29–34.[Medline]
11. Rosenberg GA, Dencoff JE, Correa N, Reiners M, Ford CC. Effects of steroids on CSF matrix metalloproteinases in multiple sclerosis: relation to blood-brain barrier injury. Neurology 1996;46:1626–1632.[Abstract]
12. Stetler-Stevenson WG. Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. Am J Pathol 1996;148:1345–1350.[Medline]


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Post by jackD » Wed Jan 13, 2010 9:04 pm

Gary A. Rosenberg, MD did more than just write the editorial in the Neurology Journal he followed it up with this great paper.

"Matrix metalloproteinases and their multiple roles in
neurodegenerative diseases
" published in Lancet Neurol 2009; 8: 205–16 ... inases.pdf


p.s This earlier study has more detail on MMPs and MS.

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Quercetin + Interferon Beta = GOOD RESULTS !!

Post by jackD » Sat Jul 10, 2010 6:55 pm

I take some QUERCETIN(500 mg) & BROMELAIN(250 mg) each day. I also eat a RED Apple each morning. This study seems to confirm that is works GREAT with Interferons.


J Neuroimmunol. 2008 Dec 15;205(1-2):142-7. Epub 2008 Oct 15.

Quercetin and interferon-beta modulate immune response(s) in peripheral blood mononuclear cells isolated from multiple sclerosis patients.

Sternberg Z, Chadha K, Lieberman A, Hojnacki D, Drake A, Zamboni P, Rocco P, Grazioli E, Weinstock-Guttman B, Munschauer F.

Department of Neurology, Baird MS Center, Jacobs Neurological Institute, Buffalo, NY 14223 , United States.

The study is aimed to determine the role of quercetin (3,3'4',5,7-pentahydroxy flavone), alone and in combination with human interferon-beta (IFN-beta), in modulating the immune response(s) of peripheral blood mononuclear cells (PBMC) isolated from multiple sclerosis (MS) patients and from normal healthy subjects.

PBMC proliferation in the presence or absence of these drugs was determined and the production of proinflammatory cytokines (IL-1beta, TNF-alpha), and the ratio of cell migration mediator MMP-9, and its inhibitor, TIMP-1 were assessed in the culture supernatants.

Quercetin reduced, in a dose-dependent manner, the proliferation of PBMC and modulated the level of IL-1beta and TNF-alpha released by PBMC in the culture supernatants.

Quercetin reduced the MMP-9/TIMP-1 ratio via lowering MMP-9 production.

Quercetin, when combined with IFN-beta, had additive effects in modulating TNF-alpha and MMP-9.

These immunomodulatory responses to quercetin were similar between MS patients and healthy control (HC) subjects.

PMID: 18926575 [PubMed - indexed for MEDLINE]
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Post by jackD » Sat Jul 10, 2010 7:05 pm

It has suddenly occurred to me that some MS folks may not know what an MMP is or what it does in MS.

So 1st here is what it does in MS.

This report published in NATURE is titled "MMPs in Biology of the Nervous System". Examine VERY carefuly Figure 2 on page 505. (my web space)

SEE FIGURE 2 and MS info on page 505

(lots of other GOOD MS STUFF here also -browse around)

I have lots of degrees but none in the medical area. I will try to simplify my ignorance and post my misunderstandings so you can fantasize about it.

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. 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 they 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 ratio.

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 deadly. Likewise taking some steroids can lower the MMP-9s quite well but can be equally deadly over the long haul.


Mult Scler. 2002 May;8(3):222-8.

Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis.

Liuzzi GM, Trojano M, Fanelli M, Avolio C, Fasano A, Livrea P, Riccio P.

Department of Biochemistry and Molecular Biology, University of Bari, Italy.

Matrix metalloproteinase-9 (MMP-9) was detected by zymography and enzyme-linked immunosorbent assay (ELISA) in matched serum and cerebrospinal fluid (CSF) samples from patients with neurological diseases.

Patients with relapsing-remitting multiple sclerosis (RR-MS) had serum and CSF MMP-9 levels comparable to those from patients with inflammatory neurological diseases (INDs), but higher than patients with non-inflammatory neurological diseases (NINDs) and healthy donors (HDs).

MMP-9 increased in active RR-MS in comparison with inactive RR-MS implying that MMP-9 in MS is related with clinical disease activity. A correlation between the CSF/serum albumin (Q(AIb)) and CSF/serum MMP-9 (Q(MMP-9)) was observed in IND and NIND but not in RR-MS patients, indicating that CSF MMP-9 levels in NIND and IND patents could be influenced by serum MMP-9 and blood-brain barrier (BBB) permeability properties.

MS patients had higher values of Q(MMP-9):Q(Alb)(MMP-9 index) than IND and NIND patients suggesting that in MS the increase in CSF MMP-9 could be due to intrathecal synthesis of MMP-9.

A significant inverse correlation was found between MMP-9 and its endogenous inhibitor TIMP-1 in RR-MS indicating that in MS patients both the increase in MMP-9 and the decrease in TIMP-1 serum levels could contribute to BBB disruption and T-lymphocyte entry into the CNS.

PMID: 12120694 [PubMed - indexed for MEDLINE]

PMID: 12120694 [PubMed - in process]
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good guys go bad!!!!

Post by jackD » Sat Jul 10, 2010 7:24 pm

Very intersting observation and opinion.


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]
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Post by jackD » Sat Jul 10, 2010 9:38 pm

Here is a rather interesting exchange I had with Ed Hill when I proposed that shutting down MMPs would be a good idea to help MS folks in Dec 2003.

I have modified my position and now only seek to lower the MMP-9 levels a Tad with selected supplements and foods/food extracts.

This is Ed Hill to me (jackD)

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

jack, 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 of a MMP as a 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

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 throughthe 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.


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?


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.

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gene transfer approach for

Post by jackD » Sun Jul 11, 2010 5:50 am

I think this gene transfer approach may be the best way to correct the MMP destructive activity problem. All mmps should have an attached TIMP. These TIMPs are "Tissue Inhibitors of MMPs" and they regulate the activities of MMPs.

So regarding the concept of MMP-9s being responsible for most myelin damage in MS, I must confess that I have never really given all the TIMPs-1 a clean bill of health.

They are suppose to insure that the MMP-9s eat ONLY the BAD STUFF.(dead/damaged/dying things)

What if they are at fault and are directing the MMP-9s to the Myelin for LUNCH?????

Traitors for sure - but is there reasonable evidence to even suspect them???


I can imagine that transplanting some "Right-thinking/Right-Acting" TIMP-1 producing genes that generate TIMP-1s which are proven MYELIN PROTECTORS would also be a good idea.
See the below abstract


Circulation. 2004 Sep 14;110(11 Suppl 1):II180-6.

Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treats ischemic cardiomyopathy.

Jayasankar V, Woo YJ, Bish LT, Pirolli TJ, Berry MF, Burdick J, Bhalla RC, Sharma RV, Gardner TJ, Sweeney HL.

Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pa 19104-4283, USA

BACKGROUND: Enhanced activity of matrix metalloproteinases (MMPs) has been associated with extracellular matrix degradation and ischemic heart failure in animal models and human patients.

This study evaluated the effects of MMP inhibition by gene transfer of TIMP-1 in a rat model of ischemic cardiomyopathy.

METHODS AND RESULTS: Rats underwent ligation of the left anterior descending coronary artery with direct intramyocardial injection of replication-deficient adenovirus encoding TIMP-1 [n=8]or null virus as control vector [n=8], and animals were analyzed after 6 weeks. Both systolic and diastolic cardiac function was significantly preserved in the TIMP-1 group compared with control animals (maximum left ventricular [LV] pressure: TIMP-1 70+/-10 versus control 56+/-12 mmHg, P<0.05; maximum dP/dt 2697+/-842 versus 1622+/-527 mmHg/sec, P<0.01; minimum dP/dt -2900+/-917 versus -1195+/-593, P<0.001).

Ventricular geometry was significantly preserved in the TIMP-1 group (LV diameter 13.0+/-0.7 versus control 14.4+/-0.4 mm, P<0.001; border-zone wall thickness 1.59+/-0.11 versus control 1.28+/-0.19 mm, P<0.05), and this was associated with a reduction in myocardial fibrosis (2.36+/-0.87 versus control 3.89+/-1.79 microg hydroxyproline/mg tissue, P<0.05). MMP activity was reduced in the TIMP-1 animals (1.5+/-0.9 versus control 43.1+/-14.9 ng of MMP-1 activity, P<0.05).

CONCLUSIONS: TIMP-1 gene transfer inhibits MMP activity and preserves cardiac function and geometry in ischemic cardiomyopathy.

The reduction in myocardial fibrosis may be primarily responsible for the improved diastolic function in treated animals.

TIMP-1 overexpression is a promising therapeutic target for continued investigation.

PMID: 15364860 [PubMed - indexed for MEDLINE]
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Re: maximizing INTERFERON-Beta effectivenes

Post by jackD » Sat Dec 10, 2011 6:50 pm

What a GREAT thread this is.

This guy is brillarnt!!


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Re: Maximizing INTERFERON-Beta effectiveness

Post by jackD » Mon Mar 12, 2012 8:59 pm

Here is the reason MS folks should avoid GRAPE SEED EXTRACT.

Increased Interferrom Gamma is VERY VERY BAD for MS folks. When they first discovered it they gave it to 10 MS folks to see if it would help them. They ALL got MUCH MUCH WORSE!


p.s. Grape SKIN EXTRACT is GREAT for MS folks. We do need some Gamma Interferon for a healthy immune system and to even repair our damaged nervous system.

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]

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