cAMP Levels & Recovery?

[Carl R]

Dr. Young, I am curious what you think about the following theory. Do you think that it's possible that most of the recovery from Dr.Huang, Dr. Lima, etc. and others could be linked simply to raising cAMP levels? My reasoning is probably too simplistic, but it seems to me that all the procedures that are currently being done are producing about the same results. It seems hard for me to attribute the results to the cells being transplanted, but maybe more about the environment from an invasive procedure. And if inflammation is a result of any procedure, and the inflammation raises cAMP levels. . . Could cAMP levels be turning on the latent axons which exist across the injury site but are not working? Could this also explain why most people are regaining function immediately when there hasn't been enough time for any axons to cross the injury site?

I wonder if Dr.Huang has seen a decrease in functional gains when using methyl prednisone in combination with OEG simply because it would inhibit inflammation and thereby reduce cAMP levels. At the other end of the spectrum would be Kawiguchi(sp), and I would assume that transections would cause a great deal of inflammation and raise cAMP levels. could this be the reason he sees such good results from transections?


I found the following Abstract which seemed to indicate that cAMP activated certain axons. Are "transmitter secretions" related to how well axons are able to work? I also found it interesting that they mentioned dibutyryl cAMP was enhanced by pretreatment with Theophylin and would assume that Rolipram would have the same effect.

lastly, What is the most effective way to measure cAMP? And would it not be beneficial to know the levels for comparison before any procedure?

I realize my conclusions are probably too simplistic, but curious what your thoughts are on why all of the invasive procedures seem to be getting about the same result?

[This message was edited by Carl R on 04-28-04 at 01:51 PM.]

[This message was edited by Carl R on 04-28-04 at 01:55 PM.]

[kilgore]

Carl:
My interpretation of the ASPET article is that they got a cat's muscle to twitch involuntarily by increasing cAMP in the bloodstream nearby. This is like making a dead frog jump with a 9-volt battery, and it doesn't look like it has any lasting effects.

That doesn't mean, however, that increasing cAMP doesn't do any good. I remember Dr. Young saying that Chris Reeve's recovery might be attributable to his exercise raising cAMP levels and that the Purdue Electric Fields might be doing the same thing. There's one abstract from the Reeve symposium that talks about getting axon sprouts on eye nerves by raising cAMP levels.

There are available medications that increase cAMP levels, including Rolipram, Albuterol, and Salmeterol. Dr. Young, are there any studies that have shown any benefits of these drugs in SCI? I saw a call for a rolipram trial for MS, but not SCI.
I know that Albuterol is common for asthma. Are there any quad asthmatics out there who are slowly recovering and just not telling anybody? Would you recommend Rolipram for those heading for Beijing? I'm tempted to start taking it just to see what happens.

Dr. Young, please correct me if any (or all) of this is wrong.

[Wise Young]

Carl R,

Marie Filbin first hypothesized and then showed that increasing cAMP levels in axons allowed them to grow in the presence of myelin-associated growth inhibitors such as Nogo and MAG, as well as extracellular matrix inhibitors such as CSPG. She proposed that rolipram would help because it blocks phosphodiesterase-4 (PDE4), the enzyme that breaks down cAMP.

Mary Bunge recently showed that contusion injury markedly reduced cAMP levels in the spinal cord, that rolipram increased cAMP levels but not back to normal, and that dibutryl cAMP (a soluble form of cAMP that can get across membranes) plus rolipram increase cAMP levels above normal and that rolipram maintained elevated cAMP levels for many days. This resulted in "massive" regeneration of axons across the contusion of the spinal cord. Although theophylline, albuterol, and salmeterol may increase cellular cAMP level, I am not aware of any studies showing that this is true of the spinal cord.

There are several ways to measure cAMP in cells: high pressure liquid chromatography, cAMP receptor fluorescent probes, radioimmunoassays, and EIA. Unfortunately, all these methods require the spinal cord for measurement.

I hope that this is helpful.

Wise.

[Carl R]

Dr. Young, I have been looking for Mary Bunge's abstract and cannot find it. I did find the following report(Transplantation Strategies) which gives a great summary of her work, but does not mention BBB scores etc. and does not say anything about " massive " regeneration. Can you point me to the abstract which mentions " massive " regeneration?

Secondly, what is the rationale for using Rolipram instead of other pd4 inhibitors which are already approved (theophylline, etc.)? What would make it any better than the others?

[Wise Young]

Carl,

The paper has not yet been published. Sometimes, it takes a long time for a paper to be accepted and published. I have seen the presentation and believe that it is one of the most important papers of the year.

Wise.

[Carl R]

Dr. Young, do you have a guess as to the second part of my last post?

what is the rationale for using Rolipram instead of other pd4 inhibitors which are already approved (theophylline, etc.)? What would make it any better than the others?

[Wise Young]

CarlR,

Theophylline is already being used in people with spinal cord injury.

Rolipram should be more specific for increasing CNS cAMP than theophylline since Rolipram specifically blocks CNS PDE4 and theophylline not only has an indirect effect but affect many other systems. By the way, there are other PDE4 inhibitors, however, besides Rolipram but because a lot of safety data exists for Rolipram (its been around for nearly three decades) and can be ordered for research, it was the easiest to study.

Wise.

[Schmeky]

This resulted in "massive" regeneration of axons across the contusion of the spinal cord.

What exactly does this mean? To much? More than the 10% we (theoretically) need?

Do the axons have to only bridge the injury site to restore function or do they have to traverse the entire length of the cord?

[Wise Young]

Schmeky,

I apologize for using the word "massive". The studies that I applied this word to include the Bunge Miami Project study using Schwann-dbcAMP-Rolipram and also the Schwann-GDNF-Chondroitinase study by Xiao Ming Xu. They both found thousands of axons (5000-10,000) growing across the injury site. The rat spinal cord probably has 50,000-100,000 axons responsible for most sensory and motor function.

Wise.

[Chris Chappell]

Carl, interesting theory.

My guess for the recovery patients are experiencing is remyelination of existing axons.

My layman's theory is that the OEG are creating better conductivity of signal through the existing axons. I'm not sure of the results but it seems, at least anecdotally, that quads are experiencing more recovery either sensory or motor. To me this indicates that the incompleteness of most quads (which seems to be more the rule than the exception these days) indicates that there are some signals, although weak, getting through. The OEG wrap themselves around these remaining axons enhancing conductivity of already existing axons.

So far the preliminary results of initial surgery / OEG implantation (i.e Huang) seem to be two levels of vertebrael(sp) descension (improvement) with the idea that the patients go back year after year for potentially increasing descension/improvement. I liken it to the OEG essentially climbing down a ladder rung (two levels at a time) by rung until the OEG have had a chance to wrap around each cervical, thoracic, lumbar and sacral level and thus improving conductivity and therefore sensory and motor function. The OEG don't creat new axons as much as potentially improve signal to muscle communication.

I keep wondering that since axon regeneration is proven and being duplicated then wouldn't the two remaining steps be axon targeting and remyelination?

Either way, through cAMP effects or myelination effects conductivity of signal seems to be improving - at least temporarily.

Interesting stuff nonetheless.