Here is a portion of what I wrote in an email to someone this morning:
I know I'm a pest about this (well, I haven't been in quite a while, I guess), but since more and more substantiation is coming out now from others with regard to (early) axonal injury in MS and the need for protection, etc., and HOW it can likely be accomplished, I still have to say that desipramine MUST have some use in progressive MS particularly!
The Netherlands are so close to my theories, it isn't even funny! And now I see Canada has jumped on board recently, also (pasted below). So, I guess I'm not completely crazy.
In addition, and I know you already know this, glutamate has also become a centralized theme in MS, along with the HPA axis in progressive MS, etc. etc. And desipramine reduces (and/or regulates) glutamate - that's a given. (Among many other MOAs that should prove beneficial for progressive types of MS........IF any of the theories about progressive MS are on-target, of course. All of which I have stated many times, so I won't reiterate.)
Anyway..................just keep it in mind.............. (Still, desipramine takes at least one year of application before any real evidence of benefit might be exhibited. AND dose is crucial.....LOW dose....has to be low dose - I'd say no more than 50 mg. a day - 75 mg. MAYBE.)
Plus, I still say if you throw in levetiracetam along with desipramine (since levetiracetam inhibits CA+ influx even better than desipramine does, AND raises BDNF better, too).............you might really have something worth looking into!
Bottom line,..............as per my prior notes, etc. etc............MAIN THEME: desipramine for axonal protection and regeneration! Levetiracetam for additional neuroprotection. (Take anything to do with me out of the picture totally. That's coincidence.) Plus, it has been found lately that desipramine shows benefit for Huntington's chorea (and not for depression, but for actual neurological application.)
Here is another substantiation below (although, I would be EXTREMELY careful about mixing desipramine with the interferons......extremely careful. But the interferons aren't of much use in progressive MS anyway, so that takes care of that. Plus, desipramine itself has immunomodulatory MOAs, and inhibits TNFa and IL1b, and raises IL10 - good for strengthening the BBB without such a high risk of adverse events; so the interferons shouldn't be all that necessary anyway.)
You have to admit, all of this almost makes MS appear to be an affective disorder, doesn't it? Pretty doggoned close!
Desipramine sure appears to be a much lower risk level for clinical trials (or bench studies) than what is being experimented with now, doesn't it? Anyway, just some renewed thoughts. Of course, nobody will get rich off of this, that's for sure.
J Neurol Sci. 2005 Jun 15;233(1-2):3-13. Related Articles, Links
General mechanisms of axonal damage and its prevention.
Division of Neuroscience, Ottawa Health Research Institute, 725 Parkdale Avenue, Ottawa, Ontario, Canada K1Y 4K9. firstname.lastname@example.org
Axonal degeneration is a prominent pathological feature in multiple sclerosis observed over a century ago. The gradual loss of axons is thought to underlie irreversible clinical deficits in this disease. The precise mechanisms of axonopathy are poorly understood, but likely involve excess accumulation of Ca ions. In healthy fibers, ATP-dependent pumps support homeostasis of ionic gradients. When energy supply is limited, either due to inadequate delivery (e.g., ischemia, mitochondrial dysfunction) and/or excessive utilization (e.g., conduction along demyelinated axons), ion gradients break down, unleashing a variety of aberrant cascades, ultimately leading to Ca overload. During Na pump dysfunction, Na can enter axons through non-inactivating Na channels, promoting axonal Na overload and depolarization by allowing K egress. This will gate voltage-sensitive Ca channels and stimulate reverse Na-Ca exchange, leading to further Ca entry. Energy failure will also promote Ca release from intracellular stores. Neurotransmitters such as glutamate can be released by reverse operation of Na-dependent transporters, in turn activating a variety of ionotropic and metabotropic receptors, further exacerbating overload of cellular Ca. Together, this Ca overload will inappropriately stimulate a variety of Ca-dependent enzyme systems (e.g., calpains, phospholipases), leading to structural and functional axonal injury. Pharmacological interruption at key points in these interrelated injury cascades (e.g., at voltage-gated Na channels or AMPA receptors) may confer significant neuroprotection to compromised central axons and supporting glia. Such agents may represent attractive adjuncts to currently available immunomodulatory therapies.
PMID: 15899499 [PubMed - indexed for MEDLINE]