Title:Effects of Novel Monoamine Oxidases and Cholinesterases Targeting Compounds on Brain Neurotransmitters and Behavior in Rat Model of Vascular Dementia
Volume: 20
Issue: 2
Author(s): Anna Stasiak, Miroslaw Mussur, Mercedes Unzeta, Abdelouahid Samadi, Jose L. Marco-Contelles and W. Agnieszka Fogel
Affiliation:
Keywords:
Permanent bilateral occlusion of the common carotid arteries, vascular dementia, monoamine oxidases’ inhibition, brain biogenic
amines’ concentration.
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.
