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Article on IL-12 and it's possible involvement in MS

One of the drugs in trial ABT-874 focuses on IL-12

http://www.scienceblog.com/cms/node/8407


Bromley

IL-12 sounds like an interesting target. Here's another treatment in trials that targets IL-12.



Agent: CNTO 1275 (monoclonal antibody) (TRIAL COMPLETED)
Purpose of study: To test safety, impact on immune function
Possible mechanism: Blocks IL-12 cytokine activity
Study description: Double blinding, placebo control, dose escalation
Dose/route: 0.3- 3.0 mg/kg sc vs. PBO
Outcome parameters: Safety, clinical response, immunogenicity, pharmokinectics
Type of MS: RR
Number of Subjects: 20
Start date: October 2003
Observation period: 28 weeks
Investigators: L. Kasper, and others
Sites: Dartmouth-Hitchcock Medical Center, Lebanon, NH, and others
Results/Publications: 1 malignant breast mass possibly related to treatment; 6 mild or moderate adverse events possibly or definitely related to Rx; no adverse events suggestive of hypersensitivity responses; T2 lesion volume and no. of Gd+ lesions similar in both groups and unaffected by dose escalation; treated patients had stable or improved EDSS scores; no relapses (Rx group) vs. 3 (PBO group)
Funding: Centocor, Inc.
Last update: 2005

http://www.nationalmssociety.org/pdf/re ... trials.pdf

thanks Bromley! This is one of the best written descriptions of the potential mechanisms for MS that I've seen. I actually understood it!

carolsue

Another IL-12 inhibitor: STA-5326 from Synta

Unlike ABT874 and CNTO1275, this one is oral. Not yet in trials for MS. Is in trials for Crohn's and psoriasis.

see:
http://www.syntapharma.com/PrdOralIL12Inhibitor.aspx

also a paper on IL-12 and MS:
http://wwwchem.csustan.edu/chem4400/sjbr/corey02.htm

gkalman,

Good post. But why are these treatments always years off from hitting the shelves? (I'm not expecting you to answer - just a rant).

Ian

Bromley wrote:Good post. But why are these treatments always years off from hitting the shelves? (I'm not expecting you to answer - just a rant).

You just have to look on the right shelves, for example, try the ones in your grocery store.

• Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.
  J Immunol. 2002 Jun 15;168(12):6506-13.

NHE

NHE wrote:

• Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes.
  J Immunol. 2002 Jun 15;168(12):6506-13.

NHE

Turmeric, also called curcumin




10:42 am

Herbs and spices can keep you healthy
11/30/2005 6:44 PM
By: Casey Taylor, News 14 Carolina
Several spices, including oregano and curry, have been found to contain beneficial antioxidants.
When you think of foods that contain antioxidants, fruits, vegetables or whole grains probably come to mind. But there's one food group you likely haven't heard about yet.

Herbs and spices pop up everywhere from garden centers to the candy aisle, but they can do more than add zip to your dish.

"Practically every herb and spice that's been studied has some health benefit," said dietician Marcia Herrin.


Herbs and spices pop up everywhere from garden centers to the candy aisle, but they can do more than add zip to your dish.
The Dartmouth Medical School nutritionist says herbs and spices are loaded with antioxidants, those chemicals that keep diseases in check. But we may not be getting those benefits as much as we could.

Herrin says Americans don't use many herbs and spices compared to the rest of the world. In India, curry is part of the staple diet. There, rates of Alzheimer's disease are the lowest in the world.

UCLA researcher and professor of medicine Sally Frautschy is studying curcumin, which is found in curry. She says it kills nearly every cancer cell in the lab.

"We accidentally found out that it blocks every single step in Alzheimer's pathogenesis," she said.

But if curry isn't your spice of choice, don't worry.


In India, curry is part of the staple diet. There, rates of Alzheimer's disease are the lowest in the world.
"There are 20 different herbs and spices, at least, that have research behind them as having health benefits," Herrin said.

Oregano leads the pack. It has 42 times more antioxidant activity than apples, 12 times more than oranges and four times more than blueberries.

Dill, sage, rosemary and ginger also rank high.

"I'm guessing we're going to end up with some really powerful medicines out of this," said Herrin.

You don't have to be a chef to reap the benefits. Just throwing a few herbs on soup or chicken is a good start.

Researchers say many of these herbs are only absorbed by the body when they are eaten with fat, so cooking with oil will help release the antioxidants.

Taking herbs and spices as a supplement in pill form will not do much for you because supplements are usually taken with water and your body cannot absorb them that way.

http://www.news14charlotte.com/content/ ... rID=107895

Melody wrote:Turmeric, also called curcumin

Just for clarity... Turmeric is the common name for the spice derived from the root of the plant Curcuma longa. Curcumin is a pigment found in turmeric with a strong antioxidant capacity (in addition to its other physiological effects - search on PubMed for more info). Documents from the World Health Organization state that the average curcumin content in turmeric is about 3%. This data is in a range consistent with data I've found from other sources. I've determined that a packed teaspoon of turmeric weighs about 3 g. Thus, using the WHO's data, there would then be about 90 mg/tsp of curcumin in turmeric. Of course, this analysis is imprecise though it does provide a "ball park" figure for comparison with the dosage recommendations found on 95% standardized curcumin supplements found in health food stores and those used in published studies found on PubMed.

NHE

Sounds very interesting.

NHE, would you mind spelling it out more explicitely. I.e., what do you believe the right dosage for MS (for IL-12 suppression) would be of Turmeric supplement, etc?

I have been watching research on tumeric and MS for a couple of years. About 3 months ago, I read another article and the researcher was excited about the aniti-inflammatory properties of tumeric.

At the end of the article, he said that no one knows how much to use daily, but determining the correct dose would be his next project.

Sorry that I don't have the article to post.

I sprinkle tumeric on my eggs, put it into soups and vegetables and mayonnaise. Either it does not have a taste or I have gotten used to it now.

gkalman wrote:would you mind spelling it out more explicitely. I.e., what do you believe the right dosage for MS (for IL-12 suppression) would be of Turmeric supplement, etc?

Actually I would mind spelling it out explicitly. I'm not a doctor and can't provide any medical advice. Nor do I believe that an internet web forum is a good source of explicit medical advice. Any person here should always check with their doctor before beginning a treatment. In fact, I believe that's stated in the "Rules of the Board," i.e., "Disclaimer: Any information you find on this site should not be considered medical advice. All decisions should be made with the consent of your doctor, otherwise you are at your own risk."

With that said, I'm still in the learning process myself, so I really have no idea. Are you a mouse with EAE or are you a human with MS? If you're an SJL/J mouse averaging around 20g in weight, than the data from the IL-12 study that I posted (which is available for free by the way) indicates that 100 µg of curcumin injected I.P. every other day looks pretty effective. If, on the other hand, you're not a mouse but a human with MS, then I'm not sure there's an answer to your question available yet. At least I haven't come across one.

If you would like to extrapolate the dosage found effective for mouse EAE to a really big mouse, maybe a human sized mouse, then you would be giving that mouse about 5mg/Kg. This human sized mouse weighs about 130 lb., so that would be around 290 mg of curcumin every other day. However, this would have to be injected I.P. to follow the guidelines of the mouse EAE paper. Of course I'm not going to do that nor do I recommend anyone else do that (as a student I worked in a DSHS office for a few months performing a mouse bio assay for paralytic shellfish toxin, we had to euthanize the mice after the assay otherwise they would die a horrid death of sepsis - we don't want to have to euthanize human sized mice, that would be ugly). Of course, the above discussion assumes that EAE in an SJL/J mouse is equivalent to MS in a human. That's probably a pretty iffy assumption unless you have pointy ears, long whiskers, and a tail (and are prone to prolific cancers and spontaneous muscle degeneration as are the SJL/J mice).

Another possible source of dosage information would be the recommendations found on the supplement bottles you find in the health food stores. One particular turmeric supplement contains 275 mg of curcumin and recommends that it be taken "one to three times daily with food." However, the question remains, would that dosage be good for MS? I don't know the answer to that either.

gwa wrote:I sprinkle tumeric on my eggs, put it into soups and vegetables and mayonnaise. Either it does not have a taste or I have gotten used to it now.

Turmeric reminds me of mustard. In fact, it's used as a colorant in inexpensive mustards such as French's. I don't happen to like mustard so consuming turmeric is not a pleasant experience for me. Maybe after a year or two it won't bother me any more (that's about how long it took for me to get used to the fishy after taste of my cod liver oil capsules).

Best wishes, NHE

from http://www.jneuroinflammation.com/content/2/1/8
The following is not specific to MS.

Apart from its ability to inhibit MIP-2 production, curcumin's pleotropic antiinflammatory and anti-oxidative properties suggest its possible use in diseases of the brain accompanied by inflammation. Thus, LPS stimulation transcriptionally upregulates inducible nitric oxide synthase and cyclooxygenase-2 genes in microglia. This leads to the synthesis of nitric oxide (NO) and prostaglandins (PGs), respectively, and the possible formation of neuron-damaging free radicals, such as peroxynitrite. Curcumin abrogates the production of both NO and PGs in LPS activated microglial cells[20]. In a recently completed Phase I clinical trial, oral curcumin at a daily dose of 3.6 grams was, in general, well-tolerated and decreased inducible PGE2 production in blood samples taken 1 hour after dose on days 1 and 29 of treatment by approximately 60%[23]. Consistent with its possible use in neurodegenerative diseases associated with oxidative stress injury, curcumin has been reported to decrease oxidative damage and amyloid deposition in a transgenic mouse model of Alzheimer's disease[24], and to reverse Aβ-induced cognitive deficits and neuropathology in rats[25].

I'm sure i read some other link that gave mice an oral dose (for EAE), and when i scaled it up it came to about 1.2g/day; but i cant find that link now.

NHE, thank you for your thoughtful post. Had no intention to offend if I did.

gkalman wrote:NHE, thank you for your thoughtful post. Had no intention to offend if I did.

No offense was taken. I realize my post may have come across a bit off. My sense of humor has been tweaked lately and a little bit of that may come through in my writing. All of the recent news about Richard Pryor's death may have been a contributing factor. I watched a segment on TV which was termed an "interview" with him. The footage was taken within the last year or so. Actually, it was more of an interview with Richard's wife while Richard was present. He didn't do much but sit in his wheel chair, nod his head once or twice, and drool. It put the potential reality of this cursed disease up front and center. I even told one of my family members of Richard's "interview" and that if all that's left of me, all that I am, is to just sit and drool, then they have my permission to shoot me and get it over with. Since then I've been thinking about Lorenzo's Oil and how Lorenzo's parents were grateful to at least have a small part of him left after they were able to halt his degradation. I guess that at this time my mind is still not made up. Perhaps the main point is to live life to its fullest and do everything humanly possible to put the brakes on this cursed disease.

NHE

Here's some more news about IL-12, this time with epigallocatechin gallate (EGCG) an antioxidant present in green tea. If lowering IL-12 levels is good for MS, and research tends to point in this direction, then I think it might be reasonable to conclude that this paper supports the hypothesis that consuming green tea would be good for MS.

• Effect of various catechins on the IL-12p40 production by murine peritoneal macrophages and a macrophage cell line, J774.1.
  Biol Pharm Bull. 2004 Sep;27(9):1353-8.

Interleukin-12 (IL-12) is a heterodimeric cytokine comprising p40 and p35 subunits produced mainly by monocytes and macrophages, and plays an essential role in the regulation of the differentiation of Th1 cells. Green tea polyphenols exhibit potent anti-oxidative activities and anti-inflammatory effects by modulating cytokine production. We investigated the effect of catechins on IL-12p40 production in murine macrophages induced by bacterial lipopolysaccharide (LPS). Pretreatment with several catechins at doses of 0.3-30 microM suppressed IL-12 p40 production by murine peritoneal exudate cells (PEC) and J774.1 cells in a dose-dependent manner. Decreases in protein production were primarily due to down-regulation of the transcription of IL-12p40 mRNA. Of the various catechins, (-)-epigallocatechin gallate (EGCG) was the most potent inhibitor, followed by (-)-gallocatechin gallate (GCG) and (-)-epicatechin gallate (ECG). EGCG inhibited LPS-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK), but not Jun N-terminal kinase (JNK), while EGCG augmented LPS-induced phosphorylation of p44/p42 extracellular signal-related kinase (ERK). In addition, both EGCG and GCG inhibited LPS-induced degradation of IkappaBalpha with concomitant inhibition of nuclear protein binding to NF-kappaB site and synthesis of IRF-1. These results suggest that gallate-containing catechins, particularly EGCG, inhibits LPS-induced IL-12p40 production in murine macrophages by inhibiting p38 MAPK while enhancing p44/p42 ERK, leading to the inhibition of IkappaBalpha degradation and NF-kappaB activation.

By the way, this paper is available for free.

NHE