Monoamine oxidase B

Differences between MAO-A and MAO-B

MAO-A generally metabolizes tyramine, norepinephrine, serotonin, and dopamine (and other less clinically relevant chemicals). In contrast, MAO-B metabolizes dopamine and β-phenethylamine, as well as other less clinically relevant chemicals. The differences between the substrate selectivity of the two enzymes are utilized clinically when treating specific disorders; MAO-A inhibitors have been typically used in the treatment of depression, whereas MAO-B inhibitors are typically used in the treatment of Parkinson's disease. Concurrent use of MAO-A inhibitors with sympathomimetic drugs can induce a hypertensive crisis as a result of excessive norepinephrine. Likewise, the consumption of tyramine-containing substances, such as cheese, whilst using MAO-A inhibitors also carries the risk of hypertensive crisis. Selective MAO-B inhibitors bypass this problem by preferentially inhibiting MAO-B, which allows tyramine to be metabolized freely by MAO-A in the gastrointestinal tract.

In 2021, it was discovered that MAO-A completely or almost completely mediates striatal dopamine catabolism in the rodent brain and that MAO-B is not importantly involved. In contrast, MAO-B appears to mediate γ-aminobutyric acid (GABA) synthesis from putrescine in the striatum, a minor and alternative metabolic pathway of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area. MAO-B specifically mediates the transformations of putrescine into γ-aminobutyraldehyde (GABAL or GABA aldehyde) and N-acetylputrescine into N-acetyl-γ-aminobutyraldehyde (N-acetyl-GABAL or N-acetyl-GABA aldehyde). These findings may warrant a rethinking of the actions of MAO-B inhibitors in the treatment of Parkinson's disease.

Roles in disease and aging

Alzheimer's disease (AD) and Parkinson's disease (PD) are both associated with elevated levels of MAO-B in the brain. The normal activity of MAO-B creates reactive oxygen species, which directly damage cells. MAO-B levels have been found to increase with age, suggesting a role in natural age related cognitive decline and the increased likelihood of developing neurological diseases later in life. More active polymorphisms of the MAO-B gene have been linked to negative emotionality, and suspected as an underlying factor in depression. Activity of MAO-B has also been shown to play a role in stress-induced cardiac damage. Over-expression and increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides (Aβ), through mechanisms of the amyloid precursor protein secretase, γ-secretase, responsible for the development of plaques, observed in Alzheimer's and Parkinson's patients. Evidence suggests that siRNA silencing of MAO-B, or inhibition of MAO-B through MAO-B inhibitors (Selegline, Rasagiline), slows the progression, improves and reverses the symptoms, associated with AD and PD, including the reduction of Aβ plaques in the brain.

Animal models

Transgenic mice that are unable to produce MAO-B are shown to be resistant to a mouse model of Parkinson's disease. They also demonstrate increased responsiveness to stress (as with MAO-A knockout mice) and increased β-PEA. In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors.

Treatment with selegiline, an MAO-B inhibitor, in rats has been shown to prevent many age-related biological changes, such as optic nerve degeneration, and extend average lifespan by up to 39%. However, subsequent research suggests that the anti-aging effects of selegiline in animals are due to its catecholaminergic activity enhancer actions rather than MAO-B inhibition.

Effects of deficiency in humans

While people lacking the gene for MAO-A display intellectual disabilities and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated phenethylamine levels in urine.

The prophylactic use of MAO-B inhibitors to slow human aging in otherwise healthy individuals has been proposed, but remains a highly controversial topic.

Selective inhibitors

Species-dependent divergences may hamper the extrapolation of inhibitor potencies.

Reversible

Natural

• Geiparvarin
• Desmethoxyyangonin, a constituent of kava extract; modest affinity
• Catechin and epicatechin.
• Garlic
• Rosiridin (in vitro)

Synthetic

• Safinamide and analogs
• 5H-Indeno[1,2-c]pyridazin-5-ones (see 3d model)
• Substituted chalcones
• 2-(N-Methyl-N-benzylaminomethyl)-1H-pyrrole
• 1-(4-Arylthiazol-2-yl)-2-(3-methylcyclohexylidene)hydrazine
• 2-Thiazolylhydrazone
• 3,5-Diaryl pyrazole
• Pyrazoline derivatives
• Several coumarin derivatives and #C19* (see 3d model)
• Phenylcoumarins, extremely subtype selective and further analogs (see 3d model)
• Chromone-3-phenylcarboxamides
• Isatins
• Phthalimides
• 8-Benzyloxycaffeines and CSC analogs
• (E,E)-8-(4-phenylbutadien-1-yl)caffeines, with A_2A antagonistic component
• Indazole- and Indole-5-carboxamides

Irreversible (covalent)

• Selegiline (Eldepryl, Zelapar, Emsam)
• Rasagiline (Azilect)