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 (Ki = 105 ± 18 μM) 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 (Ki = 0.54 ± 0.05 μM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC50 > 50 μM), 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.
Footnotes
These studies were funded by Medivation, Inc., San Francisco, California.
Medivation Inc. is developing Dimebon (latrepirdine) as a potential treatment for Alzheimer's disease and Huntington's disease. M.G., J.A.G., and A.A.P. are full-time employees of and hold stock options in Medivation Inc., San Francisco, CA; S.B. is a full-time consultant to Medivation Inc.; I.E.A. is a full-time employee of the Fundación Ciencia Para La Vida Chile, which has a research and consulting agreement with Medivation Inc.; C.D.L. is an employee of Biotrial, Rennes, France, which has a research and consulting agreement with Medivation Inc.; T.C. is a part owner of Brains On-Line, South San Francisco, CA, which has a research and consulting agreement with Medivation Inc.; C.A.A. is a full-time employee of the Alzheimer's Diagnostic Laboratory, Blanchette Rockefeller Neuroscience Institute, Rockville, MD and has a research and consulting agreement with Medivation Inc.; R.W. and B.H.-P. are full-time employees of JSW Life Sciences, Grambach, Austria, which has a research and consulting agreement with Medivation Inc.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.164491.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- AD
- Alzheimer's disease
- HD
- Huntington's disease
- AChE
- acetylcholinesterase
- NMDA
- N-methyl-d-aspartate
- ACh
- acetylcholine
- Dimebon dihydrochloride
- 2,8-dimethyl-5-[2-(6-methyl-3-pyridyl)ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
- HPLC
- high-performance liquid chromatography
- NOR
- novel object recognition
- ANOVA
- analysis of variance
- MS
- mass spectrometry
- ACSF
- artificial cerebrospinal fluid
- memantine hydrochloride
- 1-amino-3,5-dimethyladamantane hydrochloride
- GTPγS
- guanosine 5′-3-O-(thio)triphosphate
- 5-HT6
- 5-hydroxytryptamine(6)
- MK912 (L-657,743)
- (2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-one hydrochloride hydrate
- SCH23390
- R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
- Received December 22, 2009.
- Accepted February 26, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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