HYPOTHESIS: A mitochondrial mechanism contributes to neurodegeneration in multiple sclerosis (MS)
Ok..............just a real quick substantiation via another avenue that desipramine may help protect the oligodendrocytes (OLG) in MS. As I noted before, desipramine decreases "DNA fragmentation and caspase 9 and 3 activation", in addition to inhibiting TNFa. Now add that knowledge to the following:
Found out via the recent Huntington's research:
"....Because the signals that lead cells to die can come from multiple pathways, the researchers then determined which cell death pathway affected the nerve cells carrying mutant huntingtin. They found that the nerve cells' mitochondria, the parts of the cell that create energy, released a protein called cytochrome c through a pore just before dying. From other studies, it was known the drugs nortriptyline and desipramine, which are antidepressants, and trifluoperazine, an antipsychotic, block the mitochondrial pore through which cytochrome c and other death signals are released. By treating the mouse nerve cells containing the mutant huntingtin protein with these drugs, the team was able to block the nerve cells from dying. ...."
...."Therefore, factors that rescue OLG from apoptosis may increase the survival and remyelinating potential of OLG. ...."
....Apoptosis of OLG is associated with an increase in cyto-c release and caspase-9 activation
We have measured the release of cyto-c and the activation of caspase-9 in OPC in defined medium. We have detected cytoplasmic cyto-c after 24 h, and the released cyto-c level was increased significantly at 72 h. Increased cyto-c in supernatants was associated with decreased cyto-c in pellet fractions (Fig. 2A). The supernatant was free of mitochondrial contamination, as shown by the absence of cox IV in digitonin-treated samples. The absence of cyto-c in digitonin-permeabilized supernatant of the control cells (Fig. 2A, t = 0 point) also indicated that the cyto-c was released from the mitochondria affected by apoptosis, not mitochondria permeabilized by digitonin. The mitochondrial involvement was further supported by the activation of caspase-9, as shown by the generation of a 37-kDa caspase-9 cleavage fragment (Fig. 2B), a process requiring cyto-c release (50).
....We showed for the first time that apoptosis of OLG and their progenitor cells is associated with cyto-c release and caspase-9 activation. ...."
I just did a simple comparison between HD and MS. What the HD research found desipramine does as far as rescuing cells is great (and proves my point), but the problem in HD may be that in vivo desipramine does its "work" in the dentate gyrus, not the striatum, and HD appears to mainly be a disease of the striatum. Levetiracetam, though, DOES bind in the striatum and is neuroprotective (they should take a look at that one for HD, also.)
BUT, now take MS!! That rarely involves lesions in the striatum (sometimes, but pretty rare), so let's take a look again at which disease desipramine's actions will more likely assist.
I did some research a while back about logistics in MS, where the O's, axons and neurons are regenerated, etc. Take a quick look at this thread (what can I tell ya, it's easier to direct you to my online postings). Combine this with what I said the other day with regard to protection from apoptosis of the O's.
Nerve and Axonal Regeneration:
http://www.thisisms.com/modules.php?nam ... 54&start=0
Skim until you get like halfway down the page, where I start to really talk scientifically. My discussion also gets into the genetic influences. It will only take a second to look at. Interesting, huh?
..we still lack a consensus regarding the causes, pathogenesis, and mechanisms of disease progression. Current evidence indicates that multiple sclerosis is an inflammatory neurodegenerative disorder in which both adaptive and innate immunity play important roles in initiation and maintenance of the disease. Recent evidence supports the notion of molecular pathologic abnormalities beyond the plaques and dysfunction of neurons in normal appearing areas, in addition to the multifocal demyelination and axonal loss, as important features that may underlie early reversible changes in the disease. Chronic failure of remyelination, axonal regeneration, and neuronal dysfunction may contribute to disease progression….
There has been relatively little attention given to investigation of the mechanisms involved in chronic axonal loss in the progressive stages of MS. We propose a hypothesis that mitochondria play a key role in this chronic axonal loss.
Ann Neurol. 2000 Jun;47(6):707-17. Related Articles, Links
Ann Neurol. 2000 Jun;47(6):691-3.
Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination.
Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H.
Department of Neurology, Mayo Clinic, Rochester, MN, USA.
Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease--as reflected in autopsy cases--the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.
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