....The studies I would like see happen first; based on lack of current progress in that particular area of research in MS, the greatest "need" for MS patients, the largest initiative for grant funding, and the easiest to proceed on and document results of; is as I mentioned yesterday. To put it bluntly, "axonal regeneration and protection in the adult CNS".
Combining the already tested results of desipramine under one theory or hypothesis applicable to multiple sclerosis, it is highly likely that desipramine will exhibit efficacy in multiple sclerosis (due to its unique combination of MOAs), via "activating" the adult CNS in vivo to regenerate axons, retain or increase plasticity, and in the process, also show protection (or at least delaying the process enormously) of the axons from being deteriorated in the first place. The best possible evidence of this that could be measured adequately would be in "progressive" multiple sclerosis, not relapsing-remitting.
I myself do not believe full blown clinical trials with actual patients at this time would likely yield the type of efficacy that we want to be able to substantially provide evidence of.
Since there are no adequate mouse models of progressive MS at this time (of any pattern), that leaves us with lab research. That is feasible, measurable, documentable, and fairly cost effective (if there is such a thing in medical research, as we all realize).
If something positive arises from in vitro research for MS specifically, then moving it forward in vivo would then make more sense, and provide more substantive groundwork to build off of. There is no sense in jumping into something which only results in building something on "sand". A good foundation needs to be laid first, in my humble opinion. Anecdotal claims of efficacy more often than not lead nowhere, and can be basically and fairly easily dissected back down to nothing again. The same principles that apply in the legal world also apply in the medical one.
Dosage of desipramine is crucial. That fact needs to be remembered at all times. CA2+ influx is affected by desipramine (which as we know can do damage to axons), and paradoxically the dose of desipramine can cause that to go either way. It can either increase CA2+ influx or DECREASE it. Decreasing it is the way we want to go in MS. That requires careful dose of desipramine. Too much, and you tend to cancel out any probable benefits you are receiving in other areas from desipramine. (Levetiracetam, though, in combination with desipramine is another story altogether, though! Levetiracetam is HIGHLY neuroprotective because of it's EXTREME MOA for decreasing CA2+ influx, and is very synergistic with desipramine. AGAIN, not anecdotal, but shockingly coincidental! But levetiracetam does not show indications of providing disease modifying benefits, whereas desipramine does. And levetiracetam is GREAT for cognitive problems, but that drug is under patent still, and somebody will find that symptomatic efficacy eventually.) Sorry, I digress.........
Anyway, it is the "chronic low dose" application of desipramine that tells the tale.
Am I able to provide substantive material for all of the above? Yes. It's easy. Any web search on any of this will pull up lots of substantive research, but it's dissected. Each individual piece of the puzzle has to be compiled separately. Has desipramine shown that it enhances GAP43? Yes..........in connection with nothing in particular, it just showed that by itself. Has research on desipramine shown that it decreases CA2+ influx - yes, via research on that specific action by itself. Does it increase cAMP at the spinal level? Yes. And on and on. It is once you pull all the individual results together that you can see how if it TRULY does do what all of these individual conclusions have proven it does, and then compare those results to what you want to see affected in multiple sclerosis, you have a "match". An uncanny match.
Here is another example of correlations I find "off the cuff" (although this may not DIRECTLY pertain to axons, per se, but is a handy type of reference) - I don't have with me here which research publication I got this from, but......, ...
"The stimulation of immediate early gene expression in brain and neuronal cell culture systems has been reported after various experimental paradigms such as chemiconvulsant-provoked seizures or specific drug applications. In particular, the induction of immediate early genes by adrenergic model substances has been demonstrated by several investigators. This report demonstrates that a single dose of desipramine (10 or 25 mg/kg), a classical tricyclic antidepressant drug acting on the adrenergic system, induced c-fos and zif268 expression in rat hippocampus without affecting c-jun. ...."
I was intrigued, so I went farther:
"Prog Neurobiol. 2004 Nov;74(4):183-211. Related Articles, Links
A gene for neuronal plasticity in the mammalian brain: Zif268/Egr-1/NGFI-A/Krox-24/TIS8/ZENK?
Knapska E, Kaczmarek L.
Department of Neurophysiology, Nencki Institute, Pasteura 3, 02-093 Warsaw, Poland.
Zif268 is a transcription regulatory protein, the product of an immediate early gene. Zif268 was originally described as inducible in cell cultures; however, it was later shown to be activated by a variety of stimuli, including ongoing synaptic activity in the adult brain. Recently, mice with experimentally mutated zif268 gene have been obtained and employed in neurobiological research. In this review we present a critical overview of Zif268 expression patterns in the naive brain and following neuronal stimulation as well as functional data with Zif268 mutants. In conclusion, we suggest that Zif268 expression and function should be considered in a context of neuronal activity that is tightly linked to neuronal plasticity.
PMID: 15556287 [PubMed - in process]"
I hope this continues to assist with explanations for why I am pushing for testing specifically in MS for desipramine.
As a last thought, though. To make it REALLY easy, the NMSS recently granted funding to someone who claimed that keeping the immune system predominantly TH2 and raising IL10 had not yet been proven. I beg to differ completely. If we want to simply provide evidence of a drug agent that DOES to do those two things simultaneously WITHOUT even spending a DIME, we can do that. Desipramine has YEARS worth of research conclusions all showing the same thing over and over again.
Desipramine keeps the immune system response predominantly TH2 AND raises IL10 dramatically. Done deal. Proven. There went THAT good money down the drain.
Oh, well..........onward and upward. I apologize for the length of this email, but my impression is that I needed to begin presenting my case, as it were, instead of my "passion".
....In the meantime, while we reflect on what went wrong, I would like to pass on to you an essay that a friend who works with abuse victims sent to me. It was written by a woman who has spent years working as an advocate for victims of domestic abuse and she sees many parallels between her work and the reaction of many Democrats to last month’s election. Her name is Mel Giles and here is what she had to say…
.... First, you must admit you are a victim. Then, you must declare the state of affairs unacceptable. Next, you must promise to protect yourself and everyone around you that is being victimized. You don't do this by responding to their demands, or becoming more like them, or engaging in logical conversation, or trying to persuade them that you are right. You also don't do this by going catatonic and resigned, by closing up your ears and eyes and covering your head and submitting to the blows, figuring its over faster and hurts less if you don't resist and fight back.
Instead, you walk away. You find other folks like yourself, 57 million of them, who are hurting, broken, and beating themselves up. You tell them what you've learned, and that you aren't going to take it anymore. You stand tall, with 57 million people at your side and behind you, and you look right into the eyes of the abuser and you tell him to go to hell. Then you walk out the door, taking the kids and gays and minorities with you, and you start a new life. The new life is hard. But it's better than the abuse. ....
I must look like a pessimistic character, but I'd be happy if someone could prove me wrong
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