Dimebon Enhances Hippocampus-Dependent Learning in Mouse Models
of Appetitive Y-Maze and Inhibitory Step-Down Memory Tasks in Mice
Julie Vignisse
A,B,
H.W.M. Steinbusch
A, A. Bolkunov
C, J. Nunes
A,D, A.I. Santos
E, C. Grandfils
B, S. Bachurin
C, T. Strekalova
A,DA Department of Neurosciences, MHeNS, Maastricht University, Netherlands
B Department of biomedical and preclinic sciences, CEIB, University of Liege, Liege, Belgium
C IPAC, Russian Academy of Sciences, Moscow, Russia
D Center of Environmental Biology, Faculty of Sciences, Lisbon University, Lisbon, Portugal;
E Department of Physiology, Medical Faculty, New University of Lisbon, Portugal
Dimebon, a compound recently proposed for a treatment of Alzheimer’s
disorder1,2, was suggested to have memory enhancing properties in
pre-clinical studies3,4. Dimebon increased memory scores3,4,5 and enhanced
neurogenesis5 in rats.
We aimed to investigate the procognitive effects of dimebon, and to study whether repeated or acute intraperitoneal injection of this compound, at doses known to increase memory (respectively 0.1 and 0.5 mg/kg), affect learning scores in appetitive (Y-Maze) and inhibitory (step-down avoidance) tasks in 3-month-old C57BL/6N mice. Additional O-maze, novel cage, open field and water consumption tests were carried out to address possible
non-specific effects of dimebon on parameters of drinking, anxiety and
exploration/locomotion6.
2) Bolus treatment with dimebon at the dose 0.5 mg/kg
increases the performance in an inhibitory memory task in
C57BL/6N
1) Subchronic treatment with dimebon accelerates learning
and increases duration of drinking behaviour in an appetitive
memory task in C57BL/6N mice while thirst and behaviours in
other tests were not affected
• Administration of dimebon via repeated (0.1 mg/kg) and acute (0.5
mg/kg) i.p. injections respectively increases learning scores in Y-Maze and step-down avoidnace tasks in C57BL/6N mice.
• Acute treatment with dimebon at the dose 0.1 mg/kg did not affect learning scores
• No effects of 3-day administration with dimebon were observed on the parameters of thirst, anxiety, and exploration/locomotion in 3-month-old C57BL/6N mice
• Dimebon enhances hippocampus learning in both appetitive and inhibitory tasks in C57BL/6N mice
(1) O'Brien JT, Lancet Neurol 2008;7:768–9. (2) Doody RS & al., Lancet 2008;372:207–15.
(3) Giorgetti M & al., J Pharmacol Exp Ther 2010;333:748–57. (4) Schaffhauser H & al., Biochem Pharmacol 2009;78:1035–42. (5) Pieper AA & al., Cell 2010;142:39–51.
(6) Vignisse J & al., Prog Neuro-Psychopharmacol Biol Psychiatry 2011, doi:10.1016/j.pnpbp.2010.12.007
Correspondence to:
Dr Tatyana Strekalova
t.strekalova@maastrichtuniversity.nl www.unimaas.nl/mhens
School for Mental Health and Neuroscience Div. Neuroscience
T +3143 388 41 08 F +3143 367 1096
Maastricht University
P.O. Box 616
6200 MD Maastricht, The Netherlands
MHeNS, School for Mental Health and Neuroscience
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* # # # # # # # # * L a te n c y t o r e a c h w a te r re w a rd ( s ) A B 0 25 50 75 100 NaCl Dim 38/72 56/72* Chance level C o rr e c t c h o ic e s ( % )
Figure 1 : Daily administration of dimebon (0.1 mg/kg) decreases latency to reach the reward (A), and increases the percentage of correct choices for the arm with the filled bottle (B) in the Y-Maze in C57BL/6N mice. NaCl: vehicle-treated group, Dim: dimebon-treated group.
Figure 2 : Duration of drinking was significantly higher in dimebon-treated group than in control group (A) while water intake is not affected by repeated (B) or acute (C) treatment with dimebon independently of water deprivation. WD: water-deprived, nWD: non-water-deprived.
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* * * * # # # # # # # D u ra ti o n o f d ri n k in g ( s ) NaCl Dim 0 1 2 3 4 5 6 7 8 W a te r in ta k e ( m L ) Y-MAZE A C 0 1 2 3 4 5 6 7 8 nWD WD NaCl Dim + 1 h + 3 h + 24 h
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nWD WD nWD WD W a te r in ta k e ( m L ) B 30 0 50 100 150 200 30 Baseline + 1 h + 24 h #
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Good learners # # # L a te n c y o f S te p D o w n ( s ) 0 50 100 150 200 Baseline + 1 h + 24 h
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L a te n c y o f S te p D o w n ( s ) 0 25 50 75 100 NaCl Dim + 1 h + 24 h NaCl Dim 4/7 6/7 5/7 6/7 L e a rn e rs , (% ) 30 0 50 100 150 200 30 Baseline + 1 h + 24 h #
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Good learners # L a te n c y o f S te p D o w n ( s ) 0 50 100 150 200 * Baseline + 1 h + 24 h
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L a te n c y o f S te p D o w n ( s ) 0 25 50 75 100 5/15 5/15 6/15 11/15 + 1 h + 24 h
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L e a rn e rs , (% ) * A B C D E F
SDA : 3 mo C57BL/6N mice, Dim 0.1 mg/kg
SDA : 3 mo C57BL/6N mice, Dim 0.5 mg/kg
Figure 3 : C57BL/6N mice acutely treated with dimebon at the dose of 0.5 mg/kg showed significantly increased latencies of step down (E), as well as significantly higher percentage of good learners (F), 24h after training in comparison to the vehicle-treated group. A lower dose of dimebon (0.1 mg/kg) did not affect the scores of learning in C57BL/6N (B,C). NaCl Dim 0 25 50 75 100 125 150 175 200 L a te n c y o f e x it , in p e rc e n t fr o m c o n tr o l (% ) NaCl Dim 0 25 50 75 100 125 150 175 200 T im e s p e n t in o p e n a rm s , in p e rc e n t fr o m c o n tr o l (% ) NaCl Dim 0 25 50 75 100 125 150 175 200 N u m b e r o f e x it s , in p e rc e n t fr o m c o n tr o l (% ) NaCl Dim 0 25 50 75 100 125 N u m b e r o f re a ri n g , in p e rc e n t fr o m c o n tr o l (% ) O-MAZE A NOVEL CAGE C B 0 500 1000 1500 2000
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N u m b e r o f h o le s o b s e rv e d OPEN FIELD
Figure 4 : Mice repeatedly treated with dimebon did not differ from vehicle-treated animals in the O-maze (A), the novel cage (B), and in the open field (C) tests.
Y-maze apparitus Step-down avoidance
This study was supported by (ISAO) grant N 09501 to T.S., Erasmus Exchange Program of the Universities of Liege and Maastricht (to J.V.), TUL and FP6
Nanabiopharmaceuticals and the KNAW.
