Axon Regeneration and Polyamines

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Axon Regeneration and Polyamines

Postby OddDuck » Tue Feb 15, 2005 5:45 am

Not long ago, in another thread (link below), we talked about axonal regeneration:

<shortened url>

The thought is it takes not only growth factors and neurotrophins, but ALSO an elevation in cAMP at the same time in order for CNS regeneration to result.

I propose to go one step farther (based on prior research of mine). If you can also block PKC activity, inhibit Nogo-A/NgR (which is a protein that has been found to impair regeneration in the CNS after injury), and also enhance GAP-43 at the same time as increasing neurotrophins and elevating cAMP, what have you got then? The possibility or even probability of activating axonal regeneration in the adult CNS in vivo?? I'd say YES!

Just as a side note, desipramine does all of the above.

Today I find another reference regarding axonal regeneration which also brings my and Wesley's theories together. How uncanny! Here is a publication regarding axonal regeneration and polyamines. Which again, desipramine is the drug of choice that does this, also.

All I can say right now is that there are (finally) some people in MS research studying what I have found in connection to desipramine. Keep your fingers crossed.


<shortened url>

Implications for regeneration

The recent explosion in our understanding of the nature
of the myelin-associated inhibitors and how they interact
with neurons has vastly increased the number of potential
therapeutic targets. The finding that a single neuronal
receptor binds with comparable affinities and mediates
the effects of all three of the major myelin-associated
inhibitors was not only a surprise but also suggested
redundancy of activity amongst these inhibitors. In other
words, the effects of these myelin-associated inhibitors
are not cumulative but are independent of one another,
and the relative contribution of each to the block of axonal
extension will depend on their relative level of expression
at the periaxonal surface. This suggests that it may be
possible to block a single target and thereby abrogate the
inhibition of axonal regrowth by myelin and hence,
induce regeneration after injury. However, if an agent
to block the binding of inhibitors to the NgR is to be designed,
extensive knowledge of the relevant binding site(s) must be gained.

The redundancy of all three inhibitors is consistent with
findings that the effects of all myelin-associated inhibitors
can be overcome simultaneously by altering certain inte-
gral, intracellular signaling molecules. One such molecule
is the small GTPase, Rho. Blocking Rho signaling can
promote axonal regeneration both in the presence of
MAG and myelin in vitro and following CNS injury
in vivo [31]. It has been suggested that it is the interaction
of the inhibitory signaling complex with p75NTRthat
modulates Rho’s activity [29,30]. Hence, therapeutic
approaches that target the Rho signaling pathway may be
one method by which a simultaneous block of all the
major myelin-associated inhibitors could be achieved.
Two recent studies by McKerracher’s group [32,33]
indicate that this may indeed be the case. Inactivation
of Rho or its downstream effector Rho-associated kinase
(ROK) can induce improved axonal growth of primary
neurons on inhibitory substrates in vitro [32,33], and
following CNS injury, can permit increased regeneration
and functional recovery in vivo [32].

Another potential target for improving axonal regenera-
tion is the intracellular second messenger, cAMP. It has
previously been shown that increasing the levels of cAMP
can mediate a reversal of the effects of MAG on both
axonal extension [34] and growth cone turning [35]
in vitro. In addition, it has long been recognized that
inflicting a pre-conditioning peripheral lesion on DRG
neurons results in the regeneration of the CNS branch of
the same neuron when it is subsequently lesioned [36–38].
Recently, it has been suggested that CNS regeneration as
a consequence of peripheral lesioning is also mediated by
an increase in intracellular cAMP levels [39,40]. In
support of this hypothesis, studies show that microinjec-
tion of a cAMP analogue in the absence of a conditioning
lesion can mimic the regenerative effects of such a lesion.
Elevation of cAMP in vivo can also improve subsequent
axonal growth of neurons when they are cultured on
inhibitory substrates in vitro. Furthermore, we have
shown that one of the downstream components of this
signaling pathway is a synthesis of polyamines that results
from an upregulation of Arginase I, which is a key enzyme
in their synthesis [41]. Overexpression of Arginase I or
exogenous application of polyamines can mediate im-
proved axonal regeneration on myelin substrates, suggest-
ing a mechanism by which myelin-associated inhibitors
can be overcome. These findings can be explained by a
model in which the binding of a single receptor by
multiple ligands (i.e. the myelin inhibitors) initiates the
activity of the same intracellular signaling pathway(s);
thus, mechanisms that overcome the action of one inhi-
bitor may be able to overcome the inhibitory actions of all
three of the major myelin associated inhibitors. These
experiments reaffirm the idea that actions mediated by
NgR are the major inhibitory components of myelin-
associated inhibition.


There has been a recent explosion in the identification of
specific myelin-associated inhibitors, and the receptor
that mediates their actions has also been unveiled. This
represents a major leap forward in our understanding of
the contribution of the damaged myelin sheath to the
block of axonal regeneration, which occurs following
injury to the adult CNS. In addition, these findings
provide a starting point for new avenues of research,
which will result in the elucidation of the downstream
signaling components of this inhibitory complex.
Furthermore, recent evidence suggests that blockage of
the inhibitory signaling can be achieved via an elevation of
the intracellular second messenger, cAMP. This elevation
of cAMP has been shown to induce transcriptional activa-
tion and a subsequent increase in the synthesis of poly-
amines, which may play a role in this block of inhibition.
Taken together, the body of work presented in the past
year reveals a single theme: blocking a common receptor
prevents a common signaling pathway (Figure 2). This in
turn, allows for the abrogation of the effects of all of the
myelin-associated inhibitors. If applied before formation of
the glial scar, blocking th ereceptor could result in improved
regeneration and functional recovery after CNS injury.

Schematic representation of the major myelin-associated inhibitors and the proposed receptor complex that mediates their signaling. All three inhibitory molecules (Nogo-66, MAG and OMgp) bind to NgR. This in turn associates with p75NTR to transduce a signal that results in the activation of the small GTPase Rho as well as other, as yet unidentified, signaling cascades leading to the inhibition of axonal growth following injury. The intracellular upregulation of the small second messenger molecule cAMP leads to the activation of protein kinase A. This signaling cascade initiates the induction of gene transcription, including the synthesis of Arginase I, the rate limiting enzyme in the polyamine synthesis pathway. Upregulation of polyamines in turn initiates a block of the growth inhibition induced by the myelin-associated inhibitors. The small peptide NEP1-40 can bind to NgR and inhibit binding of the myelin inhibitor Nogo-66 but not of MAG.
136 Development
Current Opinion in Neurobiology 2003, 13:133–139 ....
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Postby bromley » Tue Feb 15, 2005 9:01 am


This has cheered me up - I see terms like brain atrophy and grey(why can't Americans spell properly?) matter loss etc and get very worried, and then terms like regeneration which cheers me up.

For those of us not in the know what is 'desipramine'. Would a doctor in the UK be able to precribe it? What does it do?

I hope you got lots of valentines cards - we all love you for your continuing efforts.

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Postby OddDuck » Tue Feb 15, 2005 10:19 am

Hi, bromley!!

Awwwww...........thank you SO much!!! :oops: :D You are the best!!!

Back when I was diagnosed with definite MS (which now we all know another neuro has undiagnosed me as having MS - which neither is here nor there as it pertains to how I stumbled on desipramine and the research I did), on a dare by my first neuro, I did research into desipramine to initially just prove that it affects the immune system. Finding EVERYTHING I have so far about desipramine was a shock and a surprise!

Anyway, the story has been told before on this website, so I won't bore you all again. I wrote a narrative about desipramine (i.e. conclusions that I found) that I gave to my neuro. Arron from thisisms was so kind as to post here on this website back in June: <shortened url> (Again, please note that even though the reason for my beginning this research was because we thought I had MS, also - which who knows for sure - the information regarding desipramine and levetiracetam themselves stand alone without me or my condition being a part of it at all.)

Anyway, since then, if you do a search under my name for my past postings, you'll see continual information regarding desipramine's "possible" beneficial use for MS. It is called Pertofran in the UK.

The odd thing is, it's an anti-depressant, BUT with very unusual mechanisms of action!

The second problem is, you will not be able to convince anyone to prescribe Norpramin or Pertofran (both desipramine) to you for MS. Not yet. Not off label.

I am now making some headway, though, small but sure steps, into getting the MS research community to take a serious look at desipramine and its possible (dare I say "probable") applications for MS. My main concentration right now being, as you can see, for axonal protection and regeneration. But I have to stress that nothing has been proven yet.

So, unfortunately, until more research starts being done regarding its possible applications for disease modification in MS, I'm sure it won't be able to be prescribed "off label" to anyone for that purpose at all.

That's why I'm pushing, though, for studies to be done. I have been told finally that the numerous biological background correlations I have presented do support my reasoning as to why it at least should be investigated.

In any event, as you noticed, is there quite a bit out there that indicates axonal regeneration is possible and are they close? Yes............extremely close, bromley. I can say that confidently. (For what it's worth.)

And yes, I can also reassure you that I never give up and never give in! :wink:

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