title: Effects of novel monoamine oxidases and cholinesterases targeting compounds on brain neurotransmitters and behavior in rat model of vascular dementia.
abstract: Neurodegenerative disorders are associated with different neurochemical and morphological alterations in the brain leading to cognitive and behavioural impairments. New therapeutic strategies comprise multifunctional drugs. The aim of the presented studies is to evaluate in vivo the novel compounds - ASS188 and ASS234 - which combine the benzylpiperidine moiety of the acetylcholinesteras (AChE) inhibitor donepezil and the indolyl propargylamino moiety of the monoaminooxidase (MAO) inhibitor, N-[(5-benzyloxy-1- methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine, with respect to their influence on cerebral amine neurotransmitters systems and neuroprotective activity. The presumed therapeutic potential of these compounds has been evaluated following their administration to rats with experimental vascular dementia. A rat model of the permanent bilateral occlusion of the common carotid arteries (BCCAO) and the holeboard memory test were employed for this purpose. Wistar rats were used, either intact or 1 day after BCCAO. ASS188 (1 mg/kg) and ASS234 (5 mg/kg) were given s.c. for 5 consecutive days. Working and reference memory in rats was evaluated by holeboard tests before- and 7 and 12 days after BCCAO. The activities of MAOs, AChE and histamine N-methyltransferase (HMT), as well as cerebral amines concentrations were assayed. A significant inhibition of brain MAO A (>95%) and weaker MAO B (ca 60%) and HMT (<30%) and reduced AChE activities were recorded with a pronounced (2 - 10 fold) increase in the cerebral concentrations of serotonin, dopamine, and noradrenaline and smaller rises (up to 30%) of histamine. The BCCAO rats treated with ASS188 or ASS234 tended to perform holeboard tests better than the BCCAO untreated group, indicating a beneficial effect of the administered therapeutics.
authors.forename: Anna
authors.initials: A
authors.lastname: Stasiak
authors.forename: Mirosław
authors.initials: M
authors.lastname: Mussur
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.forename: José L
authors.initials: JL
authors.lastname: Marco-Contelles
authors.affiliation: Department of Hormone Biochemistry, Medical University of Lodz, Zeligowskiego 7/9 Str., 90-752 Lodz, Poland. anna.stasiak@umed.lodz.pl.
authors.forename: W Agnieszka
authors.initials: WA
authors.lastname: Fogel
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000503:physiopathology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D002802:Cholinesterases / Q000187:drug effects / Q000378:metabolism; D015140:Dementia, Vascular / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008568:Memory / Q000187:drug effects; D008995:Monoamine Oxidase / Q000187:drug effects / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D015306:Biogenic Monoamines; D002800:Cholinesterase Inhibitors; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; C000592019:N-((5-(2-(1-benzylpiperidin-4-yl)ethoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; C570530:N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; D018696:Neuroprotective Agents; D010880:Piperidines; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002802:Cholinesterases