Can adenosine be cleared?

Question

I've been thinking about this question for awhile, since reading this question: What causes adenosine build up in the brain when awake?

We know that a couple of things will block adenosine receptors: caffeine and hops. If you're overloaded with adenosine and it's early in the day, coffee (or other caffeine sources) make you feel alert by tricking your brain by blocking the adenosine receptors. The dubious downside is that when it finally quits blocking the receptors, you've got a much bigger load of adenosine. Which might not be a downside if it means you fall asleep more easily and deeply.

But what about just clearing the adenosine?

Answer 1

In order to do this you would need to find a compound that does all of the following:

1. Crosses the blood-brain barrier. Many pharmaceuticals are not able to do this.

2. Binds strongly to, or has some metabolic effect on adenosine. The resulting product must also cross the blood-brain barrier, and be excreted.

3. Not bind or react with other molecules that are similar to adenosine and cause side effects.

4. Not cause some sort of immune response - along with the blood-brain barrier issue, this rules out any sort of protein, and really limits the potential specificity for items (2) and (3): there simply isn't a lot of chemistry outside of biochemistry that is that specific.

5. Not cause systemic effects via depletion of adenosine and products of adenosine. There are several problems caused by a failure of the enzyme that metabolizes adenosine but it seems like most of the primary symptoms are due to an accumulation of adenosine rather than an absence of inosine, so I am not certain how much of a problem this would be.

And probably numerous other issues I haven't thought of yet. The point is, adenosine is a useful biological molecule, not just junk to get rid of, and developing something to "clear" just one specific compound is actually really complicated. If the main concern is the sleepiness caused by adenosine build-up, caffeine is widely available and relatively safe compared to some novel way of actually clearing adenosine.

In fact, I can't really think of many pharmaceuticals that work by actually "clearing" something, but feel free to leave any suggestions in the comments. Chelating agents come to mind, but those are only used in some very specific circumstances.

Answer 2

As @Bryan Krause pointed out before me, unless you can regulate adenosine signaling in a selective way any manipulation is probably going to cause important side-effects.

If your goal is to regulate adenosine signaling in a more specific way than caffeine, one way could be to selectively manipulate adenosine receptors of specific pathways. This approach was taken by Blundon et al. (2017) who used a compound that is able to cross the blood-brain barrier (FR194921) to selectively affect cortical map plasticity. It so happens that this compound selectively targets thalamocortical projections, so it could be a promising strategy. But even with such a selective approach side-effects cannot be excluded.

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Full disclosure: I have contributed a preview article for that study (Kehayas and Holtmaat 2017).

<sub>References
- Blundon, J. A., Roy, N. C., Teubner, B. J. W., Yu, J., Eom, T.-Y., Sample, K. J., … Zakharenko, S. S. (2017). Restoring auditory cortex plasticity in adult mice by restricting thalamic adenosine signaling. Science, 356(6345), 1352–1356. https://doi.org/10.1126/science.aaf4612
- Feldman, D. E., & Brecht, M. (2005). Map plasticity in somatosensory cortex. Science, 310(5749), 810–815. https://doi.org/10.1126/science.1115807
- Kehayas, V., & Holtmaat, A. (2017). Rejuvenating brain plasticity. Science, 356(6345), 1335–1336. https://doi.org/10.1126/science.aan8374</sub>