Cognition-Enhancing Properties of Dimebon in a Rat Novel Object Recognition Task Are Unlikely to Be Associated with Acetylcholinesterase Inhibition orN-Methyl-d-aspartate Receptor Antagonism

Abstract

Dimebon (dimebolin) treatment enhances cognition in patients withAlzheimer'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-Daspartate (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 Ϯ 0.43, 14 Ϯ 5.1, and 172 Ϯ 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 ϭ 105 Ϯ 18 M) 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 ϭ 0.54 Ϯ 0.05 M). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC 50 Ͼ 50 M), 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.Dimebon (latrepirdine, dimebolin) is an investigational drug in Phase 3 clinical trials for the treatment of Alzheimer's disease (AD) and Huntington's disease (HD). Dimebon improved cognitive function in patients with AD during a 6-month placebo-controlled study with a 6-month open-label extension (Doody et al., 2008), and patients with HD showed some benefits in cognition in a 3-month Phase 2 study (Kieburtz et al., 2010). In the AD trial, patients treated with Dimebon also showed improvement over placebo in activities of daily living and in the behavioral and neuropsychiatric symptoms of AD, suggesting broad-based clinical improvement (Doody et al., 2008). The mechanism by which Dimebon exerts the favorable effects reported in these clinical studies is not clearly understood.Current AD therapeutics fall into two main pharmacologic classes: acetylcholinesterase (AChE) inhibitors, including donepezil, galantamine, and rivastigmine (Birks, 2006; These studies were funded by Medivation, Inc., San Francisco, California. Parts of these data were previously presented as follows: Article, publication date, and citation information can be found at

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

“…Because novelty exploration is also considered to be a rewarding stimulus, the memory enhancing effects of dimebon in the new object exploration/localization paradigms mentioned above and described by other groups (Chuhan and Taukulis, 2006;Giorgetti et al, 2010) indirectly support our findings.…”

“…In order to rule out potential confounds in the evaluation of the cognitive effects of dimebon, mice were tested in O-and Y-mazes using consistent time schedules, 15 min after drug administration in both tests. In contrast to this testing protocol, changes in the anxiety-like behaviour of dimebon-treated rats were investigated at a time point which is believed to be closer to the peak of dimebon concentration in the brain, as other studies have revealed maximal levels of the drug in the rat brain 50-60 min after its intragastrical administration at doses of 0.05-1 mg/kg (Giorgetti et al, 2010). As these doses of dimebon were similar to those used in the present study, we assume that the concentration of dimebon in the brain peaks during a comparable time period, i.e.…”

“…; Schaffhauser et al, 2009) and the novel object recognition task (0.05, 0.5 and 5 mg/kg, p.o. ; Giorgetti et al, 2010). In rats treated with the neurotoxin AF64A, which selectively lesions cholinergic neurons and impairs active avoidance, 10-day administration of dimebon reversed these deficits (1 mg/kg/day, i.p.…”

“…Ongoing clinical trials are re-assessing contradictory results (Miller, 2010) concerning the previously shown efficacy of dimebon in the improvement of thinking processes and functioning in patients with mild to moderate Alzheimer's disease Doody et al, 2008;O'Brien, 2008;Gura, 2008) and its curative effects in patients with Huntington's disease (Kieburtz et al, 2010), also during co-application with other therapeutics. Evaluation of dimebon against a set of biochemical targets indicated that dimebon inhibits alpha-adrenergic receptors (alpha1A, alpha1B, and alpha1D, and alpha2A, alpha 2B, and alpha 2C), histamine H1 and H2 receptors and serotonin receptors (5-HT-2A, 5-HT2B, 5-HT2C, 5-HT5A, 5-HT6, and 5-HT7), dopamine receptors (D, D2S, and D3), and imidazoline I2 receptors (Schaffhauser et al, 2009;Giorgetti et al, 2010). At low concentrations, dimebon potentiates the activity of AMPA-receptors and blocks NMDA-receptors in neurons (Grigorev et al, 2003).…”

“…The selection of dimebon doses used in this study are based on previous reports, which demonstrate that a single peripheral administration of the drug at a dose of 0.05-0.5 mg/kg evokes a memoryenhancing effect in rats, and results in an effective dimebon brain concentration of 1.7-14 nM/g, that was suggested to trigger neurochemical processes associated with cognitive function (Bachurin et al, 2006;Giorgetti et al, 2010). Recent studies provide evidence for a stimulatory effect by dimebon on neurogenesis in the dentate gyrus of the hippocampus in rats, observed after 1-week of intraperitoneal injections of the drug applied at the same range of concentrations: 0.1 MKM/kg (0.32 mg/kg; Pieper et al, 2010).…”