Dimebon demonstrated significant positive effects in phase II AD clinical trial conducted by Medivation in Russia [
8]. It has also demonstrated efficacy in a phase 2 trial of patients with Huntington's disease (HD) conducted by Medivation and Huntington Study Group (DIMOND). Despite extremely encouraging results in clinical trials, the mechanisms responsible for the beneficial actions of Dimebon in AD and HD remain poorly understood. Here, we evaluated neuroprotective effects of Dimebon in a previously developed cellular model of HD [
12]. We also tested the ability of Dimebon to function as a "Ca
2+ signaling stabilizer" and an inhibitor of NMDAR and voltage-gated Ca
2+ channels in Ca
2+ imaging and electrophysiological experiments with wild type and YAC128 MSN cultures. Consistent with the previous reports [
9,
10], we found that Dimebon indeed inhibits NMDAR and voltage-gated Ca
2+ channels. The IC50 for inhibitory actions of Dimebon was equal to 10 μM for NMDAR and 50 μM for voltage-gated Ca
2+ channels in our experiments (Figs
3B and
4B). At 50 μM concentration, Dimebon also exerted Ca
2+ stabilizing and neuroprotective effects in YAC128 MSN preparation (Figs
2G and
5C, Table
1). At the concentration of 10 μM, Dimebon was not effective in these
in vitro assays (Figs
2G and
5B, Table
1). Similar efficacy of Dimebon was observed in experiments with the
Drosophila model of HD [
19]. Consistent with our findings, neuroprotective effects of Dimebon in the
Drosophila model of HD were observed in the 50 – 100 μM concentration range [
19]. The protective effects of Dimebon in the
in vitro HD assay are in quantitative agreement with the "Ca
2+ stabilizing" effects of Dimebon (Fig
2G). Thus, neuroprotective effects of Dimebon observed in our experiments (Table
1, Fig
5C) most likely can be explained by "Ca
2+ stabilizing" effects of Dimebon resulting from inhibition of NMDAR (Fig
3) and voltage-gated Ca
2+ channels (Fig
4). It is also possible that Dimebon exerts additional beneficial actions at the level of neuronal mitochondria [
11]. The concentration of Dimebon required to inhibit mitochondrial permeability pore transition in isolated mitochondria was in the range of 50 μM [
11], the same concentration range as the neuroprotective effects observed in our experiments with YAC128 MSN cultures (Fig
5C, Table
1).
Using an identical experimental approach, in previous studies we demonstrated that clinically relevant NMDAR antagonist memantine (Namenda) was protective in the YAC128 MSN glutamate toxicity assay at 10 μM concentration [
13]. Thus, Dimebon is 5-fold less effective than memantine when tested in the
in vitro HD model. We also previously demonstrated that clinically relevant putative mitochondrial permeability pore inhibitors Nortriptyline, Desipramine, Trifluoperazine, and Maprotiline [
20] were also protective in YAC128 MSN toxicity assay at 2 μM concentration [
12]. The Dimebon was 25-fold less effective than these compounds when tested in the
in vitro HD model.
Unbiased evaluation of Dimebon against a set of biochemical targets indicated that Dimebon efficiently inhibits α-Adrenergic receptors (α
1A, α
1B, α
1D, and α
2A), Histamine H
1 and H
2 receptors and Serotonin 5-HT
2c, 5-HT
5A, 5-HT
6 receptors with high affinity (Fig
6). Dimebon also had significant effect on Dopamine D
1, D
2S, D
3 receptors, Imidazoline I
2 receptor, Serotonin 5-HT
2 and 5-HT
2B receptors (Fig
6). Interactions with these receptors need to be taken into consideration in interpretation of results obtained with Dimebon in HD and AD clinical trials.