Therapeutic Targets

Natural MAO Inhibitors

Monoamine oxidase is an enzyme that catalyzes the degradation of various neurotransmitters, reducing their effects in the brain and peripheral organs. There are two forms: monoamine oxidase A (MAO-A), which metabolizes norepinephrine, serotonin (5-HT), and dopamine (DA), and MAO-B, which primarily metabolizes dopamine.  

MAO inhibitors (MAOIs) were the first class of antidepressant drugs ever developed.  By blocking the enzyme, these agents enhance and prolong the mood-elevating effects of these chemical messengers.   

MAOIs are no longer in widespread use as antidepressants, owing to adverse events and problematic food-drug interactions.  Nonetheless, the enzyme continues to captivate scholarly and clinical interest, with a substantial number of publications describing natural product inhibitors in recent years. 

Many natural flavonoids and other phenolic compounds have been shown to inhibit one or both MAO isoforms (Table 1).   

Table 1. Phenolic inhibitors of monoamine oxidase in vitro.

The most potent inhibitors have the lowest IC50 values (the concentration required to achieve 50% inhibition of enzyme activity).   Flavonoids like quercetin and its analog kaempferol, and the stilbene resveratrol, were relatively effective against MAO-A, based on the above data.

Interpreting IC50 values

When reading an article describing enzyme inhibition, it’s essential to define a potent inhibitor versus a weak one. A potent inhibitor will have an IC50 value in the nanomolar range (1 nM-1 μM).  If the oral bioavailability is excellent, you might get away with a slightly higher range (1-10 μM).

Anything >100 μM is weak or ineffective. The compound might be described as an “MAO inhibitor” by the authors, within the context of the experiment, but such values strongly suggest the substance is clinically inert with respect to the target.   For example (I will spare you the math), with an oral bioavailability of <1% for curcumin, you are very unlikely to achieve 12.9 μM in the CNS of your patients.

These compounds are not what you think they are

The punchline is that MAO is probably not the mechanism of action for most of these compounds, as they exceed the nanomolar IC50 range that typifies reliable pharmacological inhibitors.

Much of our knowledge of pathophysiology and therapeutic aspirations has been shaped by an antiquated repertoire of drug targets. To understand natural products, we must move past the old “synapse” and “receptor/reuptake” framework. Only then will we find the keys to the mental health kingdom.

So, how do natural products support mood and brain health?

It will be a wad of keys too big for your hip pocket, but that’s the reality when you’re using plant-derived compounds in clinical practice. Complicated and nonspecific mechanisms are unpopular in medicine but a reality in natural therapies. They test our comfort level with chaos and the unknown. Quite truthfully, we don’t know the exact functional profile of most natural products deemed “MAO inhibitors” in the literature, but I have listed some of the most tenable mechanisms in the figure below. It’s likely that we are hitting diverse molecular targets.

Take-home points: Interpreting studies on enzyme inhibition

  1. Look for an IC50 value in the low micromolar (uM) or (ideally) in the nanomolar (nM) range, indicating strong inhibition.  Anything above 100 uM indicates weak inhibition and low translational relevance.
  2. If you’re curious about natural therapies for depression and neuroprotection, get ready to learn a few pathways and targets that you didn’t learn in medical school.
  3. Are clinical data available?   If not, take the discovery with a grain of salt.

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