MAO-B

links: MAO reference: 10-4-2021

MAO-B #

• “While people lacking the gene for MAO-A display mental retardation and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated Phenethylamine levels in urine, raising the question of whether MAO-B is actually a necessary enzyme.”

• Located in outer mitochonrial membrane.

• Catalyzes oxidative deamination and catabolism/degredation of amines (including amphetamines), but mainly Dopamine.

  • The resulting metabolites are significantly neurotoxic, as they are ROS.

• When inhibited, dopamine is metabolized using enzymes like diamine oxidase, which result in non-neurotoxic metabolites.

• Increases with aging, starting in your 50’s. (So that’s why JC said Selegiline isn’t that great until then)

• Degrades benzylamine and Phenethylamine.

• Mice unable to produce MAO are resistant to Parkinson’s.

• Inhibiting peripheral and central MAO-B ameliorates joint inflammation and cognitive impairment in rheumatoid arthritis

  • KDS2010. Reversible MAO-B inhibitor. MAO-B activates NF-κB and COX-2. IL-1β leads to, and is sufficient (necessary?) for, MAO-B-dependent GABA synthesis on astrocytes.
  • Administration of IL-1 receptor antagonist leads to reduced aberrant tonic GABA currents, indicatingb decreased GABA-A number.

• Inhibitors tend to be sedating.

GABA #

So the inhibition of GABA synthesis in the basal ganglia still, of course, disinhinibts regions like the SN.

• Glial GABA, synthesized by monoamine oxidase B, mediates tonic inhibition

  • MAO-B 60% KO or Selegiline treatment eliminated tonic GABA currents from granule neurons and MSNs.
    • Reduced Ca2+-dependent (and basal) astrocytic GABA release. A GAT inhibitor did not change this.
  • GABA content was changed, but not GABA-A receptor expressionm, since currents from agonist application were not changed,
  • Somehow, 10mg/kg (HED 116) completely inhibited MAO-B activity but did not affect MAO-A activity. Wtf?
  • Integration of quanta in cerebellar granule cells during sensory processing
    • the input layer of the cerebellum balances exquisite sensitivity with a high signal-to-noise ratio. Granule cell bursts are optimally suited to trigger glutamate receptor activation and plasticity at parallel fibre synapses, providing a link between input representation and memory storage in the cerebellum.
  • GAD is rarely expressed in glia - only in distinct neuronal populations.
  • GABA synthesis via putrescine pathway, which is MAO-B dependent.
  • GABA-T aka ABAT (4-aminobutyrate aminotransferase) catalyzes GABA into succinic semialdehyde and glutamate by transferring an amino group to GABA. Cerebellar glial cells lack this enzyme, unlike purkinje cells.
  • There are minimal tonic GABA-A currents in the hippocampus: The amount of astrocytic GABA positively correlates with the degree of tonic inhibition in hippocampal CA1 and cerebellum

• Effect of long-term treatment with selective monoamine oxidase A and B inhibitors on dopamine release from rat striatum in vivo

  • found no change of dopamine concentration in striatum acutely treated with selegiline and a small increase of dopamine on chronic treatment.

• Cat’s claw is a popular inhibitor.