title: Cognition-enhancing properties of Dimebon in a rat novel object recognition task are unlikely to be associated with acetylcholinesterase inhibition or N-methyl-D-aspartate receptor antagonism.
abstract: Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.
authors.affiliation: Medivation, Inc., San Francisco, California 94105, USA.
authors.forename: Marco
authors.initials: M
authors.lastname: Giorgetti
authors.forename: Jacqueline A
authors.initials: JA
authors.lastname: Gibbons
authors.forename: Sebastián
authors.initials: S
authors.lastname: Bernales
authors.forename: Iván E
authors.initials: IE
authors.lastname: Alfaro
authors.forename: Christophe
authors.initials: C
authors.lastname: Drieu La Rochelle
authors.forename: Thomas
authors.initials: T
authors.lastname: Cremers
authors.forename: C Anthony
authors.initials: CA
authors.lastname: Altar
authors.forename: Robert
authors.initials: R
authors.lastname: Wronski
authors.forename: Birgit
authors.initials: B
authors.lastname: Hutter-Paier
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Protter
mesh_terms: D000109:Acetylcholine / Q000378:metabolism; D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors; D003071:Cognition / Q000187:drug effects*; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007189:Indans / Q000494:pharmacology; D007211:Indoles / Q000097:blood / Q000494:pharmacology*; D008297:Male; D008559:Memantine / Q000494:pharmacology; D017551:Microdialysis; D010880:Piperidines / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011969:Receptors, Histamine H1 / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000037:antagonists & inhibitors*; D021641:Recognition, Psychology / Q000187:drug effects*
chemical_list: D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D007189:Indans; D007211:Indoles; D010880:Piperidines; D011969:Receptors, Histamine H1; D016194:Receptors, N-Methyl-D-Aspartate; D000077265:Donepezil; D000110:Acetylcholinesterase; D000109:Acetylcholine; C010119:latrepirdine; D008559:Memantine