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Journal of Neuroscience, Vol 12, 1977-1999, Copyright © 1992 by Society for Neuroscience
Quantitative enzyme radioautography with 3H-Ro 41-1049 and 3H-Ro 19- 6327 in vitro: localization and abundance of MAO-A and MAO-B in rat CNS, peripheral organs, and human brain
J Saura, R Kettler, M Da Prada and JG Richards
F. Hoffmann-La Roche Ltd., Pharma Division, Basel, Switzerland.
Monoamine oxidases A and B (MAO-A and MAO-B) oxidatively deaminate
neurotransmitter and xenobiotic amines. Since the cellular localization of
the isoenzymes in the CNS and peripheral organs determines to a large
extent which substrate has access to which isoenzyme, knowledge of their
tissue distribution and cellular localization is essential. Here we
describe how reversible and selective inhibitors of MAO-A and MAO-B [Ro
41-1049 and Ro 19-6327 (lazabemide), respectively] can be used, as
tritiated radioligands, to map the distribution and abundance of the
enzymes in microscopic regions of the rat CNS and peripheral organs, and
human brain by quantitative enzyme radioautography. The in vitro binding
characteristics of both radiolabeled inhibitors revealed them to be
selective, high-affinity ligands for the respective enzymes. KD and Bmax
values for 3H-Ro 41-1049 in rat cerebral cortex were 10.7 nM and 7.38
pmol/mg protein, respectively, and for 3H-Ro 19-6327 were 18.4 nM and 3.45
pmol/mg protein, respectively. In accordance with their potencies as enzyme
inhibitors, binding to MAO-A and MAO-B was competitively inhibited by
clorgyline (IC50 = 1.4 nM) and L-deprenyl (selegiline; IC50 = 8.0 nM),
respectively. The capacities of various rat and human tissues to bind the
radioligands correlated extremely well with their corresponding enzyme
activities. As revealed by the respective binding assays, the distribution
and abundance of MAO-A and MAO-B in the tissues investigated differed
markedly. MAO-A was most abundant in the locus coeruleus, paraventricular
thalamus, bed nucleus of the stria terminalis, median habenular nucleus,
ventromedial hypothalamus, raphe nuclei, solitary tract nucleus, inferior
olives, interpeduncular nucleus, claustrum, and numerous peripheral
tissues, including liver, vas deferens, heart, superior cervical ganglion,
and exocrine and endocrine pancreas. In contrast, MAO-B was most abundant
in the ependyma, circumventricular organs, olfactory nerve layer,
periventricular hypothalamus, cingulum, hippocampal formation, raphe
nuclei, paraventricular thalamus, mammillary nuclei, cerebellar Bergmann
glia cells, liver, posterior pituitary, renal tubules, and endocrine
pancreas. The cellular localization of the isoenzymes in both rat and human
brain differs markedly and does not reflect the distribution of the
presumed natural substrates, for example, absence of MAO-A in
serotoninergic neurons. Indeed, the present evidence suggests that, whereas
MAO-A is found in noradrenergic and adrenergic neurons, MAO-B occurs in
astrocytes, serotoninergic neurons, as well as ventricular cells, including
most circumventricular organs. The physiological roles of the enzymes are
discussed in the light of these findings, some of which were
unexpected.(ABSTRACT TRUNCATED AT 400 WORDS)
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