Nerve repair

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Nerve repair

Postby bromley » Mon Jul 25, 2005 2:28 am

Dear all,

Some hopeful news from the BBC website. Doesn't specifically mention MS but testing on humans could be within the next year.

Bromley





http://news.bbc.co.uk/1/hi/health/4707023.stm
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Postby OddDuck » Mon Jul 25, 2005 5:50 am

Hi, Bromley!

Glutamate...........yeah, that appears to pop up as a factor in just about every neurological disease.

You know, there are already quite a few agents on the market now that help block and/or regulate glutamate.

It's just getting neuros to prescribe those things off-label to MSers that is the problem.

Deb
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Postby OddDuck » Mon Jul 25, 2005 5:55 am

And here I go again............. :wink:

Here is just ONE of those agents (my pet drug of all time....hehehe...):



Biochem Biophys Res Commun. 2005 Jul 29;333(2):622-7. Related Articles, Links


Linking tricyclic antidepressants to ionotropic glutamate receptors.

Stoll L, Gentile L.

Department of Chemistry, Western Washington University, Bellingham, WA 98225-9150, USA.

Although tricyclic antidepressants have been in existence since the 1940s when they were discovered upon screening iminodibenzyl derivatives for other potential therapeutic uses, their mechanism of action has remained unclear [A. Goodman Gilman, T.W. Rall, A.S. Nies, P. Taylor, Goodman and Gilman's The Pharmacological Basis of Therapeutics, eighth ed., Pergamon Press, New York, 1990]. In addition to their ability to hinder the reuptake of biogenic amines, there is mounting evidence that the tricyclic antidepressants inhibit glutamate transmission. Here, intrinsic tryptophan fluorescence spectroscopy is used to document the binding of desipramine, a member of the tricyclic antidepressant family, to a well-defined extracellular glutamate binding domain (S1S2) of the GluR2 subunit of the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor. The binding is distinct from those of other known effectors of the receptor, including the endogenous sulfated neurosteroids pregnenolone sulfate and 3alpha-hydroxy-5beta-pregnan-20-one sulfate, and is consistent with a conformational change upon binding that is allosterically transmitted to the channel region of the receptor.

PMID: 15946644 [PubMed - in process]
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Postby bromley » Mon Jul 25, 2005 5:59 am

OddDuck,

I knew the mention of glutamate would wake you up!

All the best

Bromley
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Postby OddDuck » Mon Jul 25, 2005 6:00 am

:lol:

I have today off from work, and I'm bored. :wink:

Deb
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Postby OddDuck » Mon Jul 25, 2005 6:10 am

You know, bromley. They (i.e. researchers) are getting closer with regard to researching desipramine in direct relationship to neurological diseases (just not MS yet). The NMSS speculated to me that they thought it wouldn't be long anyway before someone besides me stumbles onto this, even though nobody is listening to me. (I can hardly wait to say to all the people I contacted, especially Vanderbilt, to say I TOLD YOU SO!! :lol: )

I stumbled on this article not long ago. But I've been good. I haven't been hounding anybody about it. Yet, that is. :wink:

This combines the Ca2 issue (that we've discussed many times before on here) AND glutamate:



Proc Natl Acad Sci U S A. 2005 Feb 15;102(7):2602-7. Epub 2005 Feb 3. Related Articles, Links

Disturbed Ca2+ signaling and apoptosis of medium spiny neurons in Huntington's disease.

Tang TS, Slow E, Lupu V, Stavrovskaya IG, Sugimori M, Llinas R, Kristal BS, Hayden MR, Bezprozvanny I.

Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Huntington's disease (HD) is caused by polyglutamine expansion (exp) in huntingtin. Here, we used a yeast artificial chromosome (YAC) transgenic mouse model of HD to investigate the connection between disturbed calcium (Ca2+) signaling and apoptosis of HD medium spiny neurons (MSN). Repetitive application of glutamate elevates cytosolic Ca2+ levels in MSN from the YAC128 mouse but not in MSN from the wild-type or control YAC18 mouse. Application of glutamate results in apoptosis of YAC128 MSN but not wild-type or YAC18 MSN. Analysis of glutamate-induced apoptosis of the YAC128 MSN revealed that (i) actions of glutamate are mediated by mGluR1/5 and NR2B glutamate receptors; (ii) membrane-permeable inositol 1,4,5-trisphosphate receptor blockers 2-APB and Enoxaparin (Lovenox) are neuroprotective; (iii) apoptosis involves the intrinsic pathway mediated by release of mitochondrial cytochrome c and activation of caspases 9 and 3; (iv) apoptosis requires mitochondrial Ca2+ overload and can be prevented by the mitochondrial Ca2+ uniporter blocker Ruthenium 360; and (v) apoptosis involves opening of mitochondrial permeability transition pore (MPTP) and can be prevented by MPTP blockers such as bongkrekic acid, Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline. These findings describe a pathway directly linking disturbed Ca2+ signaling and degeneration of MSN in the caudate nucleus in HD. These findings also suggest that Ca2+ and MPTP blockers may have a therapeutic potential for treatment of HD.
PMID: 15695335 [PubMed - indexed for MEDLINE]
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Postby OddDuck » Mon Jul 25, 2005 6:15 am

Ya know.............what if my first neuro WAS correct, and I DO have MS. Remember, the second opinion I got was quite a while AFTER I had taken the medication I'm on and had recovered. My first neuro even said no other doctor was gonna see MS at that point. Plus, my second appointment was with Vanderbilt, and they tend to undiagnose most people anyway (that's out of their OWN mouths).

I'm not "cured".............I just have been able to keep "it", whatever it is, under control now.

*sigh* Guess we might never know. Strange, huh?

Deb
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Postby finn » Mon Jul 25, 2005 6:36 am

Sorry, time to leave the board.

-finn
Last edited by finn on Sun Aug 28, 2005 2:38 pm, edited 1 time in total.
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Postby bromley » Mon Jul 25, 2005 6:42 am

Deb,

I posted the article from the BBC website today - they also have a list of older articles. One mentions an anti-depressant (see articles) but does not name it.

http://news.bbc.co.uk/1/hi/northern_ireland/3614134.stm



Ian
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Postby OddDuck » Mon Jul 25, 2005 6:42 am

Hey.............Hi, Finn!!!

You know, you'd think that with all of this already on the market, etc., at SOME point somebody could just sit down, do an in-depth "intellectual" analysis based on everything that is already known about many of these chemical agents, and simply say "Ok............let's try THIS combination for this or that patient".

Heck.........that's all I did when choosing my particular medication "cocktail".

Of course, you know that I know that nothing is ever that simple.

But geez, even Dr. Sam Hunter used to say "keep it simple". I say "practice what you preach, doctors"....... :wink:

Deb
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Postby OddDuck » Mon Jul 25, 2005 6:45 am

Hey, bromley! I almost could have written that press release myself, huh? (i.e. the second one you just now posted for us.)

Ok..........you did it now, bromley. I'm on the "hunt"........... :wink:

Deb
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Postby bromley » Mon Jul 25, 2005 6:53 am

Deb,

I totally agree with you on this. There seems to be many drugs on the market that may have real value in halting this disease. But someone needs to map out or model what we know about this disease to identify the ways in which these drugs might help.

A classic example is minocycline. Last May we were told about the trial in Calgary for a small sample of ms sufferers which had good results. 16 months later a research paper is published which sets out the mechanisms.for this drug. As Finn has pointed out there has been lots of research on this drug for some time. But nothing ever really comes of it. No doubt next year the researchers will produce more papers etc. If it got any slower it would be going backwards. Neuros only ever offer up the ABCRs and don't seem to think wider than this.

There's 160 trials going on at present and articles often say that there's never been a better time to get MS (2050 would be a better time for me). But it's annoying when there are possible drugs already available but know one seems very bothered (the pharma companies for obvious reasons).

Bromley
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Postby OddDuck » Mon Jul 25, 2005 6:57 am

Ahhhhhh.................I found it.

Dr. Filbin (in that second article you just posted, bromley) is talking about Rolipram. Remember Rolipram?? I rambled on about that early on. I even compared desipramine with rolipram in my very first original narrative I posted on here. They do the same thing regarding raising cAMP.

She's right, though. Plus...........get this. With desipramine's additional mechanisms of action that rolipram doesn't have, PLUS the fact that you CAN combine desipramine with rolipram (research has found they work together), you might REALLY have something.

Taking rolipram alone, though, doesn't work because you can't take enough rolipram alone that is required for the beneficial effects to happen without the side effects becoming too overwhelming, BUT as I say about desipramine, it's the COMBINATION with other chemical agents that counts.

Again, she's (Dr. Filbin) right! (Based on my non-expert research experience, that is.)

Deb
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Postby OddDuck » Mon Jul 25, 2005 7:01 am

....But it's annoying when there are possible drugs already available but know one seems very bothered (the pharma companies for obvious reasons).


So true, bromley! Hence why I finally threw up my hands and said "I give up". It was way too frustrating!

Deb
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Desipramine etc.

Postby Brainteaser » Tue Jul 26, 2005 8:15 pm

I find this fascinating research by Bromley & OddDuck (& Finn)!

So, where do we go from here? I have just got my desipramine and have been starting it at 25mg. Do we get rolipram and if so, what dosage should we ask our doctors to prescribe? Is there anything else to add to the 'Bromduck Combo'? How about minocycline as mentioned by Finn?

Regards & thanks for your efforts,
Phil.
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