limited potentiation of blood pressure in response to oral tyramine by the anti-Parkinson brain selective multifunctional monoamine oxidase-AB inhibitor, M30.
One of the limitations of non-selective monoamine oxidase (MAO) inhibitors as anti-depressant or anti-Parkinson drugs is their ability to potentiate the cardiovascular effect of oral tyramine, resulting from inhibition of systemic MAO-A and release of noradrenaline. We have investigated the cardiovascular effect of oral tyramine in response to the novel multifunctional, brain selective MAO-AB inhibitor, M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline], and compared it to the classical non-selective inhibitor tranylcypromine (TCP) in rats. We also measured MAO-A and B in the striatum, hippocampus, liver, and small intestine and determined brain levels of dopamine, noradrenaline, and serotonin. At the doses employed, intraperitoneal (i.p.) M30 (5 and 10 mg/kg) selectively inhibited brain MAO-A and B by more than 85%, with little inhibition of liver and small intestine enzymes while raising striatal levels of dopamine, noradrenaline, and serotonin. In contrast to TCP (10 mg/kg, i.p.), which fully inhibits both enzymes in the brain and systemic organs and significantly potentiates the tyramine pressor effect, M30 had a limited pressor effect as compared to it and controls. The limited potentiation of tyramine pressor effect by M30, its ability to raise brain levels of aminergic neurotransmitters together with its neuroprotective and neurorestorative activities make this drug potentially important as an anti-depressant and anti-Parkinsonian agent, for which it is being developed.
Gal
Shunit
S
Department of Pharmacology, Technion-Rappaport Family Faculty of Medicine, Eve Topf and US National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases, Efron St, PO Box 9697, Haifa 31096, Israel.
Abassi
Zaid A
ZA
Youdim
Moussa B H
MB
D000284:Administration, Oral; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006912:Hydroxyquinolines / Q000494:pharmacology*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D014191:Tranylcypromine / Q000494:pharmacology; D014439:Tyramine / Q000008:administration & dosage / Q000494:pharmacology*
C517687:5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline; D000978:Antiparkinson Agents; D006912:Hydroxyquinolines; D008996:Monoamine Oxidase Inhibitors; D012701:Serotonin; D014191:Tranylcypromine; D008995:Monoamine Oxidase; D004298:Dopamine; D009638:Norepinephrine; D014439:Tyramine