title: Effects of novel tacrine-related cholinesterase inhibitors in the reversal of 3-quinuclidinyl benzilate-induced cognitive deficit in rats--Is there a potential for Alzheimer's disease treatment?
abstract: Inhibitors of cholinesterase are important drugs for therapy of Alzheimer's disease and the search for new modifications is extensive, including dual inhibitors or multi-target hybrid compounds. The aim of the present study was a preliminary evaluation of pro-cognitive effects of newly-developed 7-MEOTA-donepezil like hybrids (compounds no. 1 and 2) and N-alkylated tacrine derivatives (compounds no. 3 and 4) using an animal model of pharmacologically-induced cognitive deficit. Male Wistar rats were subjected to tests of learning and memory in a water maze and step-through passive avoidance task. Cognitive impairment was induced by 3-quinuclidinyl benzilate (QNB, 2mgkg(-1)), administered intraperitoneally 1h before training sessions. Cholinesterase inhibitors were administered as a single therapeutic dose following the QNB at 30min at the following dose rates; 1 (25.6mgkg(-1)), 2 (12.3mgkg(-1)), 3 (5.7mgkg(-1)), 4 (5.2mgkg(-1)). The decrease in total path within the 10-swim session (water maze), the preference for target quadrant (water maze) and the entrance latency (passive avoidance) were taken as indicators of learning ability in rats. The effects of novel compounds were compared to that of standards tacrine (5.2mgkg(-1)) and donepezil (2.65mgkg(-1)). QNB significantly impaired spatial navigation as well as fear learning. Generally, the performance of rats was improved when treated with novel inhibitors and this effect reached efficiency of standard donepezil at selected doses. There was a significant improvement in the groups treated with compounds 2 and 3 in all behavioral tasks. The rest of the novel compounds succeed in the passive avoidance test. In summary, the potential of novel inhibitors (especially compounds 2 and 3) was proved and further detailed evaluation of these compounds as potential drugs for Alzheimer's disease treatment is proposed.
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic. Electronic address: misik@pmfhk.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Misik
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Korabecny
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors.forename: Eugenie
authors.initials: E
authors.lastname: Nepovimova
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors.forename: Alzbeta
authors.initials: A
authors.lastname: Kracmarova
authors.affiliation: University of Defence, Faculty of Military Health Sciences, Department of Toxicology and Military Pharmacy, Trebesska 1575, 500 01, Hradec Kralove, Czech Republic.
authors.forename: Jiri
authors.initials: J
authors.lastname: Kassa
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000523:psychology; D000077265:Donepezil; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D018727:Muscarinic Antagonists; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D011813:Quinuclidinyl Benzilate; D017208:Rats, Wistar; D013619:Tacrine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D007189:Indans; D018727:Muscarinic Antagonists; D010880:Piperidines; D013619:Tacrine; D011813:Quinuclidinyl Benzilate; D000077265:Donepezil
keywords: 7-MEOTA; Acetylcholinesterase; Donepezil; Passive avoidance; Water maze