• 作者：Carolina Birgner ; Anna M.S. Kindlundh-Hö ; gberg ; Lars Orel ; Johan Alsiö ; Jonas Lindblom ; Helgi B. Schiö ; th ; Lena Bergströ ; m
• 关键词：Anabolic androgenic steroid ; Monoamine oxidase ; Nandrolone decanoate
• 刊名：Brain Research
• 出版年：2008
• 期刊代码：8_00068993
• 类别：neu
• 出版时间：11 July 2008
• 卷：1219
• 期：Complete
• 页码：103-110
• 文件大小：315 K

Two isoenzymes, namely MAO-A and MAO-B, were first identified by their inhibitor sensitivity and substrate selectivity and later by differences in their primary structure. In human brain, serotonin and noradrenaline are presumed to be preferentially metabolized by MAO-A, the trace amine phenethylamine and tele-methylhistamine by MAO-B, and tyramine, octopamine as well as dopamine by both enzymes. Reversible inhibitors of MAO-A (RIMAs; prototype: moclobemide) are effective antidepressants with unusually low side-effect profiles. Lazabemide, a selective reversible inhibitor of MAO-B has therapeutic potential for the treatment of Parkinson's disease (as add-on therapy with L-dopa), as well as Alzheimer's disease.

Knowledge of the brain distribution of these enzymes is important since their tissue compartmentation and cellular localization determine to a large extent which substrate has access to which isoenzyme. Moreover, disease-related changes in enzyme distribution could provide a rationale for drug therapy. Previous studies have used enzyme histochemical and immunohistochemical techniques to map the distribution of MAOs in rodent and human brain. The recent development of two high resolution assays - in situ hybridization histochemistry (using enzyme-selective oligonucleotide probes) to map the sites of enzyme synthesis and quantitative enzyme radio enzyme radioautography (using enzyme-selective reversible inhibitors, Ro 41-1049 and lazabemide [Ro 19-6327] for MAO-A and-B, respectively) to map the abundance of analytic sites and their de novo synthesis - has enabled more extensive cellular and quantitative analyses to be carried out. Moreover, in an attempt to create an animal mode of oxidative stress, we have generated transgenic mice over-expressing MAO-B (up to 4-fold) under the regulation of the neuron-specific enolase promoter.

COMT: COMT is a Mg²⁺-requiring enzyme which catalyzes the transfer of a methyl group from S-adenosyl-L-methionine to the meta(para)hydroxy groups of compounds containing a catecholamine moiety, including the neurotransmitters dopamine, adrenaline and no-radrenaline. Immunohistochemical investigations have revealed that the enzyme is present not only in peripheral organs, e.g. liver, kidney, intestine, but also in discrete regions of the CNS (notably not in dopaminergic neurons). Its presence in blood-brain and brain-CSF interfaces suggests a barrier function for the enzyme, preventing uncontrolled access of catechols to the brain. These findings have been recently confirmed in our laboratory by transcript mapping which, moreover, demonstrated high levels of mRNA in hippocampal pyramidal neurons, dentate gyrus granule cells, as well as lower brainstem and spinal cord motoneurons.

The enzyme - catalyzing one of the major degradative pathways of catecholaminergic neurotransmitters - is a target of therapeutic drugs for Parkinson's disease. Tolcapone (Tasmar®, Ro 40-7592), for example, is a highly potent, reversible, selective, orally active and well tolerated COMT inhibitor, currently in advanced phase III of clinical development for the treatment of Parkinson's disease (add-on therapy with Madopar® or Sinemet®). Accumulation of 3-O-methyldopa, the inactive metabolite of levodopa formed by COMT, has been associated with reduced transport of levodopa into the brain and also with the ‘wearing-off’ phenomenon. Tolcapone, by inhibiting the peripheral metabolism of 1-dopa, increases the availability of the latter for transport and conversion into dopamine in the brain. It has been shown to increase the efficacy and prolongs the duration of 1-dopa response in animal models of Parkinson's disease.