Banisteriopsis caapi / Harmalas MAO-B inhibition?

[endlessness]

So it is generally quoted as an established fact that harmalas are selective MAO-A inhibitors

Sources:

Gerardy, J. (1994) Effect of moclobemide on rat brain monoamine oxidase A and B: Comparison with Harmaline and Clorgtline
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Volume 18, Issue 4, July, Pages 793-802 (Can anybody get the full file?)



Bergström et al (1997) C-harmine as a tracer for monoamine oxidase a (MAO-A): In vitro and in vivo studies
Nuclear Medicine and Biology, Volume 24, Issue 4, May 1997, Pages 287-293 (attached to post)

Ginovart N, Meyer JH, Boovariwala A, et al. (2005) Positron emission tomography quantification of [11C]-harmine binding to monoamine oxidase-A in the human brain. J Cereb Blood Flow Metab. 2005;26(3):330-344. (also attached to post)

Son, SY. "Structure of human monoamine oxidase A at 2.2-Å resolution: The control of opening the entry for substrates/inhibitors" PNAS April 15, 2008 vol. 105 no. 15 5739-5744 (also attaching)



But I also distinctly remember reading about harmalas in high doses being less selective and also inhibiting MAO-B, but I really cant find the source for this. Then researching more about it, I came across the following article:



Samoylenko V et al (2010) Banisteriopsis caapi, a unique combination of MAO inhibitory and antioxidative constituents for the activities relevant to neurodegenerative disorders and Parkinson’s disease
J Ethnopharmacol. 2010 Feb 3;127(2):357-67. (attached below too, VERY interesting publication)

Now notice they do say there is some MAO-B binding, both from harmalas (harmine, harmaline and THH), but also from two proanthocyanidines anti-oxidant compounds found in caapi (epicatechin and procyanidin B2). Amongst other quotes from the paper:

Harmaline (6) and harmine (7) showed potent in vitro inhibitory activity against recombinant
human brain monoamine oxidase (MAO)-A and -B enzymes (IC50 2.5 and 2.0 nM, and 25 and 20 μM,
respectively), and (−)-epicatechin (8) and (−)-procyanidin B2 (9) showed potent antioxidant and mod-
erate MAO-B inhibitory activities (IC50 < 0.13 and 0.57 ug/mL, and 65 and 35 μM)

The problem is Im not well versed enough in biochemistry/pharmacology to know if the values of MAO-B inhibition at μM is considerable or not.


So, is this MAO-B inhibition significant, or is it not? What does this mean to us ?

 

[rOm]

Kava kava inhibit the MAO B, as long as I understood.
I too wonder how about inhibit A and B while spicing up ?!

 

[Infundibulum]

Endlessness, the IC50 values for enzyme inhibition are inversely correlated with inhibition strength. IC50 is the concentration of the inhibitor that will cause 50% of enzyme inhibition. The less the value, the more potent the inhibitor.

The quoted values mean that harmaline and harmine are 10,000 more potent MAO-A inhibitors compared to MAO-B (e.g. MAO-A IC50/MAO-B IC50 = 2nm/20μm). It also says that harmaline is 20% weaker than harmaline at inhibiting either enzymes. Epicatechin and procyanidin are a tad weaker from either harmine and harmaline with IC50s of 65 and 35μM.

Before drawing any conclusions it is important to mention that these enzyme kinetics were done in purified human brain MAO enzymes which may not reflect what happens with MAO enzymes elsewhere in the body. Different enzyme isoforms that may exist in the liver/stomach/guts etc will have different values. Different physiological conditions within individuals (let's say enzyme modifications not found in such in vitro experiments that make enzymes more or less prone to such inhibition in vivo) will also affect what actually happens.

In my opinion this level of inhibition does not mean much to us. It would if we knew that, say MAO-B enzymes are, say 10,000 less abundant than MAO-A, which I do not think is the case.

 

[joedirt]

Following up on Infundibulum's post.

If you want to visualize the IC50's relative to each other in a linear fashion you need to plot the inverse log of the IC50 values.

We do this when we are trying to make correlations between structure (or some molecular property) and activity. This allows us to perform a linear regression analysis.

Let me try to phrase that slightly different. When you look at a dose-response curve it typically follows the shape of an S or sigmoidal curve. There is a region in the middle that is fairly linear, but the ends are more exponential or logarithmic depending on which side of the curve one is looking at. By converting these values to the inverse log we are able to flatten the curve and use linear correlation techniques.

Why do this?

Well a compound with an IC50 of 10 is not necessarily going to illicit a response that is twice as strong as a compound with an IC50 of 20... remember the curves go exponential in on direction and logarithmic in another direction. Are 5 grams of mushrooms twice as potent as 2.5 grams? Certainly not fo me! 5 grams is debilitating and uncomfortable. 2.5 grams is barely enough to illicit CEVs. To get a better view of relative responses one can expect form drugs the IC50's need to linearized so the values can be compared in a direct linear fashion.

Peace

 

[endlessness]

Excellent posts Infundibulum and Joedirt, thanks a lot for this

 

[Ginkgo]

Gerardy, J. (1994) Effect of moclobemide on rat brain monoamine oxidase A and B: Comparison with Harmaline and Clorgtline
Progress in Neuro-Psychopharmacology and Biological Psychiatry
Volume 18, Issue 4, July, Pages 793-802 (Can anybody get the full file?)

Cheers!