MORE ON DESIPRAMINE (ceramide, bdnf, sodium density)

If it's on your mind and it has to do with multiple sclerosis in any way, post it here.

MORE ON DESIPRAMINE (ceramide, bdnf, sodium density)

Postby OddDuck » Sun Oct 31, 2004 8:06 am

Hi, folks. Well, it has been a while since I’ve promoted the testing of desipramine for MS, and another thread this morning got me thinking I should check to see if anything new has come out lately, and sure enough. Here’s what I found.

We all are aware of how it is believed that ceramide plays a role in MS. The hypothesis is that you ideally would want to inhibit ceramide. Well, read this. We’ll start with just a few (I could find more, but no need) of the findings regarding ceramide and cell death
:


FROM THE NMSS RESEARCH WEBSITE:

Ceramide in rafts (detergent-insoluble fraction) mediates cell death in neurotumor cell lines

Kilkus J, Goswami R, Testai FD, Dawson G

Journal of Neuroscience Research 2003 Apr 1;72(1):65-75

What does it mean? The authors identify an important step in the death of nerve cells, such as that which occurs in MS.

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J Neurosci Res. 2003 Apr 1;72(1):65-75.

Ceramide in rafts (detergent-insoluble fraction) mediates cell death in neurotumor cell lines.

Kilkus J, Goswami R, Testai FD, Dawson G.

Departments of Pediatrics, Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 30637, USA.

Detergent-resistant lipid microdomains (Rafts) were isolated from human oligodendroglioma (HOG), human neuroblastoma (LA-N-5), and immortalized dorsal root ganglion (F-11) cell lines by sucrose-density gradient ultracentrifugation and shown to be enriched in cholesterol, sphingomyelin, and ceramide. [(3)H]palmitate labeling allowed the Raft fraction to be easily identified as a sharp peak of (3)H radioactivity in the 5-30% sucrose interphase. Treatment of [(3)H]palmitate-labeled cells with staurosporine (to activate caspase 8 and induce apoptosis) or exogenous sphingomyelinase specifically increased the [(3)H]ceramide content of the Raft fraction. Depletion of cholesterol with beta-methylcyclodextran decreased Raft formation and partially blocked staurosporine-induced apoptosis. Similarly, treatment of cells with Fumonisin B1 to inhibit de novo sphingolipid synthesis by 50% reduced the labeling of the Raft fraction and partially blocked staurosporine-induced apoptosis. Staurosporine treatment activated neutral sphingomyelinase but had no effect on acid sphingomyelinase activity or on other lysosomal hydrolases, such as alpha-L-fucosidase. Most of the neutral sphingomyelinase activity is in the Raft fraction, suggesting that the conversion of sphingomyelin to ceramide in Rafts is an important event in neural cell apoptosis. Copyright 2003 Wiley-Liss, Inc.

PMID: 12645080 [PubMed - indexed for MEDLINE]

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THIS IS FROM THE UNIVERSITY OF KANSAS. KIND OF INTERESTING:

© 1997 Higuchi Biosciences Center of Excellence. Permission is granted to copy and distribute this information provided that this copyright statement accompanies such distribution.

The Higuchi Biosciences Center, a KTEC Center of Excellence, is a family of research centers at the University of Kansas.

Neurotrophin-Induced Cell Death
Investigator: Rick T. Dobrowsky

Goals:
To investigate the molecular mechanisms which regulate neuronal growth

Brief Description of the Project:
Nerve growth factor (NGF) is a well characterized growth factor which classically has been involved in promoting cell growth and survival. However, recent results from the investigator’s lab and others indicate that NGF can also induce cell death. Thus, it is important to understand what factors dictate whether a cell responds by growing or dying after it binds NGF. These studies have direct applicability to understanding mechanisms operative in demyelinating diseases since one of the prime targets for NGF-induced cell death are the cells which are responsible for myelination of nerves within the central nervous system. Myelination of nerves is necessary for neural conduction. Demyelination leads to progressive dysfunction such as seen in multiple sclerosis. The investigator has been studying the signal transduction pathways that lead to nerve growth factor induced death in certain cells of the nervous system.

Status of the Project:
The investigator has determined that NGF induces the production of ceramide which is associated with the onset of cell death. He is currently trying to identify how ceramide kills the cells. Understanding this process will inevitably aid in the development of strategies to interfere with neurodegenerative conditions associated with demyelination. Also, control of the ceramide-initiated cascade of events in neurons may provide a useful target for drug intervention in diseases that exhibit enhanced rates of programmed cell death.

Commercialization Prospects:
This is an early phase project aimed at identifying cell targets which may be involved in regulating neurodegeneration. This project may be linked in the future to other projects focused on treatments for neurodegenerative diseases, such as Alzheimer’s disease or ALS.

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J Exp Med. 1996 Dec 1;184(6):2361-70.

Multiple sclerosis: Fas signaling in oligodendrocyte cell death.

D'Souza SD, Bonetti B, Balasingam V, Cashman NR, Barker PA, Troutt AB, Raine CS, Antel JP.

Neuroimmunology Unit, McGill University, Montreal Neurological Institute, Quebec, Canada.

Fas is a cell surface receptor that transduces cell death signals when cross-linked by agonist antibodies or by fas ligand. In this study, we examined the potential of fas to contribute to oligodendrocyte (OL) injury and demyelination as they occur in the human demyelinating disease multiple sclerosis (MS). Immunohistochemical study of central nervous system (CNS) tissue from MS subjects demonstrated elevated fas expression on OLs in chronic active and chronic silent MS lesions compared with OLs in control tissue from subjects with or without other neurologic diseases. In such lesions, microglia and infiltrating lymphocytes displayed intense immunoreactivity to fas ligand. In dissociated glial cell cultures prepared from human adult CNS tissue, fas expression was restricted to OLs. Fas ligation with the anti-fas monoclonal antibody M3 or with the fas-ligand induced rapid OL cell membrane lysis, assessed by LDH release and trypan blue uptake and subsequent cell death. In contrast to the activity of fas in other cellular systems, dying OLs did not exhibit evidence of apoptosis, assessed morphologically and by terminal transferase-mediated d-uridine triphosphate-biotin nick-end-labeling staining for DNA fragmentation. Other stimuli such as C2-ceramide were capable of inducing rapid apoptosis in OLs. Antibodies directed at other surface molecules expressed on OLs or the M33 non-activating anti-fas monoclonal antibody did not induce cytolysis of OLs. Our results suggest that fas-mediated signaling might contribute in a novel cytolytic manner to immune-mediated OL injury in MS.

PMID: 8976190 [PubMed - indexed for MEDLINE]

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HERE ARE SOME SUBSTANTIATIONS THAT DESIPRAMINE DECREASES CERAMIDE (not only from one pathway of activation of ceramide, but from a couple different ones, indicating once again a broad spectrum of efficacy) EVEN THOUGH THIS ARTICLE IS REGARDING ATHEROSCLEROSIS, NOTICE THE MENTION OF THE GOOD OLE “CASPASE” CASCADE OF EVENTS, ALSO, WHICH AGAIN CORRELATES WITH MS:

Originally published In Press as doi:10.1074/jbc.M209179200 on May 15, 2003

J. Biol. Chem., Vol. 278, Issue 27, 24399-24408, July 4, 2003

Oxidized Low Density Lipoprotein Inhibits Macrophage Apoptosis by Blocking Ceramide Generation, Thereby Maintaining Protein Kinase B Activation and Bcl-XL Levels*

Rajinder S. Hundal, Antonio Gómez-Muñoz, Jennifer Y. Kong , Baljinder S. Salh, Anthony Marotta, Vincent Duronio and Urs P. Steinbrecher ||

From the Department of Medicine, University of British Columbia, Vancouver V5Z 3P1, Canada, and the Department of Biochemistry and Molecular Biology, University of the Basque Country, P. O. Box 644, 48080 Bilbao, Spain

Macrophages play a central role in the development and progression of atherosclerotic lesions. It is well known that oxidized low density lipoprotein (ox-LDL) promotes the recruitment of monocytes (which differentiate to macrophages) into the intima. We reported recently that ox-LDL blocks apoptosis in bone marrow-derived macrophages deprived of macrophage colony-stimulating factor (M-CSF) by a mechanism involving protein kinase B (PKB) (Hundal, R., Salh, B., Schrader, J., Gómez-Muñoz, A., Duronio, V., and Steinbrecher, U. (2001) J. Lipid Res. 42, 1483–1491). The aims of the present study were 1) to define the apoptotic pathway involved in the pro-survival effect of ox-LDL; 2) to determine which PKB target mediated this effect; and 3) to identify mechanisms responsible for PKB activation by ox-LDL. Apoptosis following M-CSF withdrawal was accompanied by activation of the caspase 9-caspase 3 cascade and cytochrome c release from mitochondria, but the caspase 8 pathway was unaffected. M-CSF withdrawal resulted in a marked and selective reduction in Bcl-XL protein and mRNA levels, and this decrease was prevented by ox-LDL. The ability of ox-LDL to preserve Bcl-XL levels was blocked by NF B antagonists, thereby implicating I B kinase as a key PKB target. M-CSF deprivation resulted in activation of acid sphingomyelinase and an increase in ceramide levels. Desipramine (a sphingomyelinase inhibitor) prevented the increase in ceramide and inhibited apoptosis after M-CSF deprivation. Ox-LDL completely blocked the increase in acid sphingomyelinase activity as well as the increase in ceramide after M-CSF deprivation. Pretreatment of macrophages with C2-ceramide reversed the effect of ox-LDL on PKB and macrophage survival. These results indicate that ox-LDL prevents apoptosis in M-CSF-deprived macrophages at least in part by inhibiting acid sphingomyelinase. This in turn prevents ceramide-induced down-regulation of PKB, the activity of which is required to maintain production of Bcl-XL.

***************************************

J Natl Cancer Inst. 2004 Sep 1;96(17):1288-99.

Comment in:
•J Natl Cancer Inst. 2004 Sep 1;96(17):1264-5.

Gangliosides link the acidic sphingomyelinase-mediated induction of ceramide to 12-lipoxygenase-dependent apoptosis of neuroblastoma in response to fenretinide.

Lovat PE, Di Sano F, Corazzari M, Fazi B, Donnorso RP, Pearson AD, Hall AG, Redfern CP, Piacentini M.

Northern Institute for Cancer Research, University of Newcastle upon Tyne, Newcastle upon Tyne, UK.

BACKGROUND: The lipid second messenger ceramide, which is generated by acidic and neutral sphingomyelinases or ceramide synthases, is a common intermediate of many apoptotic pathways. Metabolism of ceramide involves several enzymes, including glucosylceramide synthase and GD3 synthase, and results in the formation of gangliosides (GM3, GD3, and GT3), which in turn promote the generation of reactive oxygen species (ROS) and apoptosis. Fenretinide, a retinoic acid derivative, is thought to induce apoptosis via increases in ceramide levels, but the link between ceramide and subsequent apoptosis in neuroblastoma cells is unclear. METHODS: SH-SY5Y and HTLA230 neuroblastoma cells were treated with fenretinide in the presence or absence of inhibitors of enzymes important in ceramide metabolism (fumonisin B1, inhibitor of ceramide synthase; desipramine, inhibitor of acidic and neutral sphingomyelinases; and PDMP, inhibitor of glucosylceramide). Small interfering RNAs were used to specifically block acidic sphingomyelinase or GD3 synthase activities. Apoptosis, ROS, and GD3 expression were measured by flow cytometry. RESULTS: In neuroblastoma cells, ROS generation and apoptosis were associated with fenretinide-induced increased levels of ceramide, glucosylceramide synthase activity, GD3 synthase activity, and GD3. Fenretinide also induced increased levels of GD2, a ganglioside derived from GD3. Inhibition of acidic sphingomyelinase but not of neutral sphingomyelinase or ceramide synthase, blocked fenretinide-induced increases in ceramide, ROS, and apoptosis. Exogenous GD3 induced ROS and apoptosis in SH-SY5Y cells but not in SH-SY5Y cells treated with baicalein, a specific 12-lipoxygenase inhibitor. Exogenous GD2 did not induce apoptosis. CONCLUSIONS: A novel pathway of fenretinide-induced apoptosis is mediated by acidic sphingomyelinase, glucosylceramide synthase, and GD3 synthase, which may represent targets for future drug development. GD3 may be a key signaling intermediate leading to apoptosis via the activation of 12-lipoxygenase.

PMID: 15339967 [PubMed - indexed for MEDLINE]
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HERE IS JUST A NEW FINDING REGARDING HOW DESIPRAMINE PROVIDES NEUROPROTECTIVE BENEFITS BY INCREASING LEVELS OF BDNF (WHICH WE KNOW IS BENEFICIAL IN MS). OH, AND AS A SIDE NOTE, I MYSELF TOOK A ROUND OF STEROIDS WHILE I WAS TAKING DESIPRAMINE. NOW I’M THINKING I’M GLAD I WAS ON DESIPRAMINE AT THE TIME, BECAUSE IF THERE WAS ANY CHANCE OF THE STEROID ITSELF DOING ANY DAMAGE TO NEURONS, IT WAS PREVENTED BY DESIPRAMINE, (WHILE NOT AFFECTING THE STEROID'S BENEFICIAL AFFECTS.)

Brain Res. 2004 Nov 12;1026(2):157-67.

Chronic antidepressant medication attenuates dexamethasone-induced neuronal death and sublethal neuronal damage in the hippocampus and striatum.

Haynes LE, Barber D, Mitchell IJ.

Biomedical Science, Medical School, The University of Nottingham, Queens Medical Centre, E70, Nottingham NG7 2UH, United Kingdom.

Dexamethasone, a synthetic corticosteroid, which can induce a range of mood disorders including depression and affective psychosis, is toxic to specific hippocampal and striatal neuronal populations. Chronic administration of antidepressants can induce neuroprotective effects, potentially by raising cellular levels of brain-derived neurotrophic factor (BDNF). We accordingly tested the hypothesis that chronic pretreatment of rats (Sprague-Dawley, male) with antidepressants would attenuate dexamethasone-induced neuronal damage as revealed by reductions in the level of neuronal death and in sublethal neuronal damage shown by the increase in the number of MAP-2 immunoreactive neurons. In support of this hypothesis, we demonstrate that chronic treatment with a range of antidepressants prior to dexamethasone administration (0.7 mg/kg, i.p.) attenuated the levels of neuronal death and loss of MAP-2 immunoreactivity in both the hippocampus and striatum. The antidepressants used were: desipramine (8 mg/kg, i.p., tricyclic), fluoxetine (8 mg/kg, i.p., selective serotonin reuptake inhibitor) and tranylcypromine (10 mg/kg, i.p., monoamine oxidase inhibitor) with each drug being injected once per day for 10 days. In contrast, acute injection of none of the antidepressants exerted a protective effect from dexamethasone-associated neuronal damage. Similarly, injection of neither cocaine nor chlordiazepoxide (benzodiazepine) exerted protective effects when injected either chronically or acutely. The observed protection from dexamethasone-induced neuronal damage is in keeping with the potential of chronic antidepressant medication to increase BDNF levels. The potential for dexamethasone to induce disorders of mood by damaging specific neuronal populations in the hippocampus and dorsomedial striatum is discussed.

PMID: 15488477 [PubMed - in process]
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HERE IS JUST ANOTHER “NEW’ SUBSTANTIATION THAT DESIPRAMINE HELPS MAINTAIN SODIUM DENSITY, WHICH AS WE KNOW FROM MANY RESEARCHERS’ FINDINGS, IS HIGHLY BENEFICIAL IN PREVENTING PERMANENT DAMAGE IN MS. THIS ARTICLE IS GEARED TO PAIN REDUCTION, BUT THE SODIUM CHANNEL BLOCKING EFFECT IS OF NOTE FOR MS:

Pain. 2004 Nov;112(1-2):106-12. Related Articles, Links

Intrathecal tri-cyclic antidepressants produce spinal anesthesia.

Chen YW, Huang KL, Liu SY, Tzeng JI, Chu KS, Lin MT, Wang JJ.

Department of Medical Research, Chi-Mei Medical Center, Tainan, Taiwan, ROC; Institute of Physiology, National Yang-Ming University Medical College, Taipei, Taiwan, ROC.

Tri-cyclic antidepressants (TCAs) have been widely used in treating major depressive disorders. Recent studies further demonstrated that TCAs have potent sodium channel blocking effect, and amitriptyline, one of the TCAs, has a potent spinal anesthetic effect. The aim of the study was to evaluate the spinal anesthetic effect of various TCAs and to see whether these TCAs could likewise act as local anesthetics after a single intrathecal injection. Bupivacaine, a potent and long-acting traditional local anesthetic, acted as control. The spinal anesthetic effect of nine TCAs (amitriptyline, doxepin, imipramine, trimipramine, clomipramine, protriptyline, desipramine, nortriptyline, and amoxapine) and three traditional local anesthetics (bupivacaine, lidocaine, and mepivacaine) was evaluated in rats and so were dose-response studies of amitriptyline, bupivacaine, and lidocaine. Under a given concentration of 5mM, bupivacaine had the most potent spinal blockade of motor, propioception, and nociception (P<0.001) and the longest duration of action of nociception (P<0.01) among the three traditional local anesthetics. Under this concentration, amitriptyline had a similar potency but longer duration of spinal blockade of motor, propioception, and nociception (P<0.001) than did bupivacaine, whereas several other TCAs had similar or less potencies of spinal blockade than did bupivacaine. In dose-response studies, amitriptyline had a more potent (P<0.005) and longer duration (P<0.001) of spinal blockade than did bupivacaine. We concluded that intrathecal amitriptyline had a more potent and longer duration of spinal anesthetic effect than did bupivacaine, whereas several other TCAs had similar or less potencies than did bupivacaine.

PMID: 15494190 [PubMed - in process]

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SO AGAIN, I SAY…………WILL SOMEBODY PLEASE TEST DESIPRAMINE FOR MS!!!??

Deb
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Postby OddDuck » Sun Oct 31, 2004 10:41 am

I thought I'd better post a "reminder" from my other posts over the past few months.

DOSAGE OF DESIPRAMINE IS CRUCIAL. If you take the (large) dose of desipramine as is needed in order to treat depression, that is too much to provide the beneficial effects needed for the hypothesized MS therapy.

Again, this was substantiated in previous posts of mine relating to dosage of desipramine. If you go too high on dose, you end up getting an opposite effect from the one you get if you stay on the lower end of dosage. It's a paradox, BUT it has been substantiated in laboratory testing. And it goes along with Philip's (mscaregiver) notation that the only thing that differentiates between a beneficial treatment and a poison is the dose.

I just wanted to remind folks of that fact. It's all in the "dose".........and in the length of time of therapy (chronic vs. acute). It's the low dose "chronic" use of desipramine that produces the probable NUMEROUS beneficial regulatory effects for MS.

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Desipramine/ fluoxetine combination

Postby VickiG » Mon Nov 01, 2004 11:42 am

Thank you again, Deb, for your on-going investigation of desipramine. As we've discussed before, combining fluoxetine (Prozac) with a tricyclic like desipramine results in an over-increased serum level of desipramine. And as you have stated, this dosage would be too high for ms treatment.
BUT, if one wanted to continue fluoxetine treatment for depression and add desipramine appropriate for ms, have you seen any dosage recommendations or research? Would serum testing for desipramine and then some trial and error adjustments be the only course? And what is the proposed serum level of desipramine appropriate for benefit to ms?

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Postby OddDuck » Mon Nov 01, 2004 12:19 pm

Nope......I haven't seen any research (myself) at all, Vicki. That's another conundrum. HAH! Actually, right now, trial and error IS the only course. That's why I'm pushing for research trials.

AND the problem with desipramine is that you cannot adequately detect its levels via serum testing alone. It sort of hides. It's taken up in tissue and cells, but doesn't really register much in serum. Serum levels are very unreliable. (I researched that, also, when trying to assure my own safety when taking it, i.e. how we might be able to monitor its levels. I was taking it for the first time in combination with another drug, so I wanted to know what methods I could use to keep track of what was going on with it. I explained that to my first neuro, too. He wanted to start me higher, and I said no, because taking desipramine in combination might prove risky, so I started lower than normal, and told him to give it a few weeks to see first. He said "Ok".)

It can be a hidden "danger", shall we say - the levels of desipramine rising when used in just any old combination therapy. But I see you came to many of the same conclusions I did. If you are very careful about not "mixing" desipramine haphazzardly, then in and of itself, it appears to be a pretty safe drug. Especially at the lower doses. I've had consensus on that from ALL of the doctors I've spoken to.

I'm no doctor, mind you, and of course, that's one of the reasons why desipramine would have to go through clinical testing first and why I'm pushing for it - the unknowns at this time. Especially regarding appropriate dosage, etc. I can't "recommend" a thing at all.

I will say, though, that even though "I" personally push for extreme caution (with my two doctors..........my PCP, and my "new" neuro) when prescribing an SSRI with a TCA, my neuro said they "do it all the time". I just literally cringed, and said "Ewwww.......) LOL I told him he better double-check doing that with desipramine!

All I can say is that I am on 50 mg. of Norpramin (desipramine) taken at bedtime, along with 2,000 mg. of Keppra (levetiracetam) a day. And I suffer from no side effects at all. Virtually none. BUT....that doesn't mean that would hold true for everyone!

Taking desipramine with fluoxetine, though, personally sort of makes me hesitate. (And they were both discovered by the same man, too. Dr. Fridolin Sulser.) Hey, Vicki...........try this!

Dr. Sulser is currently a Department Head at Vanderbilt University. Email him and see what he says!

Remember, I'm taking desipramine for other symptoms than symptoms solely arising from MS. And we can't use me at all for any kind of anecdotal evidence of anything. The initial process of me researching desipramine came about solely from a challenge between myself and my previous neuro. Neither one of us had any idea what I would really find. We both were shocked.

Desipramine's indication for MS is purely based on other researchers' findings over the years, and compiled by me "on paper". Hence, why I keep pushing for somebody to put it in research studies for MS.

BUT.....am I saying anyone should just go out and ask their doctors to prescribe it for them for MS? No. That would be an "off label" use, and to use it for MS therapy at all is not proven in any manner whatsoever.

And ethically, I can't and wouldn't advise anyone trying to get it prescribed to them FOR MS therapy, either. (And I mentioned earlier in my initial narrative and subsequent postings that I personally found that there's extreme caution to be used when prescribing desipramine in conjunction with ANY of the MS injectables. Frankly, even I wouldn't do that combo.)

My initiative is simply providing enough justification to get it put into valid, ethical, legal, medical clinical trials.

If your doctor wants to give it a shot, though, that would of course be between you and him personally. That would be his risk to take. But again (and I know you would) but I have to reiterate..............honesty is the best policy.

This is directed to anyone and everyone: Do NOT go into a doctor's office and "fake" depression in order to try desipramine for MS. Honesty is always the best policy.

I'm sorry.............I probably wasn't much help here, was I? Just long-winded again, huh? (I hope I didn't "lecture" too much?)

:?

Deb

EDIT: I need to clarify. I posted at an earlier time where it was simply found in general terms how a lower dose of desipramine does something different than a higher dose, so I guess I did find some "outside" research, but it wasn't focused on MS at all. It's posted here somewhere. It was just enough, though, to justify my initial hypothesis (which was based on only my "gut feelings" at the time) that a lower dose of desipramine would prove more effective. That correlation is posted on this website in another thread somewhere. :)
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Postby OddDuck » Mon Nov 01, 2004 12:34 pm

Ok.....here it is:

http://www.thisisms.com/modules.php?nam ... opic&t=230

I posted what I found on June 23, 2004. (It was another one of my "here's how I got there" exercises. :wink: ) You'll need to skip past all the posts between me and Willy "debating". LOL

It was regarding how different doses of desipramine affect calcium influx. And that was what initially led me to believe I was on the right track in thinking that a lower dose of desipramine was better for MS.

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Postby carolsue » Sun Nov 21, 2004 2:03 pm

Deb,
What are your thoughts re: Raynaud's phenomenum (vasospasms affecting primarily the fingers) co-occurring with MS, and the role of calcium influx. Raynaud's, which is treated w/ nifedipine (a calcium channel blocker), frequently co-occurs with a variety of disorders, including MS.

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Postby OddDuck » Sun Nov 21, 2004 3:32 pm

Hi, Carol!

Well, I'm no doctor, of course, but I have heard of Raynaud's. To my understanding, it's basically vascular spasms, to put it simply. From what I remember, though, these specific types of spasms appear to result from exposure to the cold, and is connected with the sympathetic nervous system. Let me go take a quick look at a few things.

Ok..........It appears that a definite causal relationship has not been found, but as you noted, it seems to often be a secondary condition in relationship to other autoimmune diseases. Here is one theory about Raynaud's that I found interesting:

‘Local fault’ theory

Lewis first proposed the ‘local fault’ theory in 1929, following cold-induced vasoconstriction in RS subjects despite previous digital sympathectomy (Turton et al., 1998). The theory proposes that blood vessels are abnormally sensitive to the cold. A congenital or acquired abnormality in expression of alpha 1- and alpha 2-adrenoceptors (which control digital vasoconstriction) may provide reason for increased sensitivity to cold exposure as seen in RS (Flahavan, cited in Sheperd and Sheperd, 1993, p. 159). Heightened alpha 1-adrenergic sensitivity or density have been found in subjects with RS (Belch, 1997; Coffman, 1989; and Keenan and Porter, cited in Sheperd and Sheperd, 1993, p. 159). Alternatively, inadequate alpha 1-adrenoceptor function with resultant aalpha 2-adrenoceptor dominance (Sheperd and Sheperd, 1993). With cooling, presynaptic beta -adrenoceptors may be hypersensitive, leading to increased noradrenaline output from the nerve terminal (Coffman, 1989; and Sheperd and Sheperd, 1993).

Bunker and colleagues (1996) suggest the axon reflex that mediates vascular response of the skin may be impaired in RS.


There is our "adrenal" connection again (i.e. norepinephrine, aka noradrenaline). :? And the relationship between Raynaud's and MS happening together quite often can help lend credence to the theory that if you locate the commonality(ies) between the two, you may have additional justification and a fairly valid avenue for pursuing further research into that specific commonality. The quandary between the two conditions existing together, though, due to a bit of opposite polars (for lack of a better term) as mentioned in the above article, would probably result in surmising that there may be a "regulatory" dysfunction happening.........the origination of which apparently hasn't been traced yet. It lies within the "nerves" according to theory. So......it might be logical to assume that if you could control nervous system "regulation" of vascular constriction, you would be able to keep Raynaud's under control (?)

I personally wonder if the damage or regulatory control for secondary Raynaud's that exists with MS doesn't actually lie more in specific type or location of "axonal" dysfunction, though.

I'm not certain what thoughts you might be looking for (?)

It makes perfect sense to me that a condition like this might occur along with MS, due particularly to the apparent similarities and overlaps of the physiological dysfunctions that have been postulated is happening in both MS and Raynaud's. Hence, the calcium influx commonality and treatment (e.g. assistance with axonal damage).

Maybe I can lend you my thoughts more precisely if I had more detail regarding what questions you might have?

:D

And of course, I can't, wouldn't, and am not even knowledgeable enough, even if I could, give actual medical "advice".

Deb
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Postby carolsue » Tue Nov 23, 2004 11:15 pm

OddDuck wrote:It makes perfect sense to me that a condition like this might occur along with MS, due particularly to the apparent similarities and overlaps of the physiological dysfunctions that have been postulated is happening in both MS and Raynaud's. Hence, the calcium influx commonality and treatment (e.g. assistance with axonal damage).


Thanks Deb, this is pretty much what I was looking for in terms of your thoughts. The overlap between RS and MS was starting to make sense to me as I was reading your posts, and I was curious if I was on the right track. Molecular biology is still quite a mystery to me...
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Postby OddDuck » Wed Nov 24, 2004 5:07 am

Hi, Carol! You're welcome.

Yea, it's still a mystery to just about everybody, I believe!

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