Pharmacological characterization of memoquin, a multi-target compound for the treatment of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by progressive loss of cognitive function, dementia and altered behavior. Over 30 million people worldwide suffer from AD and available therapies are still palliative rather than curative. Recently, Memoquin (MQ), a quinone-bearing polyamine compound, has emerged as a promising anti-AD lead candidate, mainly thanks to its multi-target profile. MQ acts as an acetylcholinesterase and β-secretase-1 inhibitor, and also possesses anti-amyloid and anti-oxidant properties. Despite this potential interest, in vivo behavioral studies with MQ have been limited. Here, we report on in vivo studies with MQ (acute and sub-chronic treatments; 7-15 mg/kg per os) carried out using two different mouse models: i) scopolamine- and ii) beta-amyloid peptide- (Aβ-) induced amnesia. Several aspects related to memory were examined using the T-maze, the Morris water maze, the novel object recognition, and the passive avoidance tasks. At the dose of 15 mg/kg, MQ was able to rescue all tested aspects of cognitive impairment including spatial, episodic, aversive, short and long-term memory in both scopolamine- and Aβ-induced amnesia models. Furthermore, when tested in primary cortical neurons, MQ was able to fully prevent the Aβ-induced neurotoxicity mediated by oxidative stress. The results support the effectiveness of MQ as a cognitive enhancer, and highlight the value of a multi-target strategy to address the complex nature of cognitive dysfunction in AD.

Figure 1. MQ rescues scopolamine-induced spatial memory deficits.

Effect of MQ treatment on spontaneous alternation behavior (A) and MWM (B) in a scopolamine-induced amnesia model in mice. In the T-maze, MQ (7–15 mg/kg , p.o.) was administered 20 min before scopolamine (1 mg/kg, i.p.); in the MWM, MQ (7 and 15 mg/kg, p.o.) was administered 20 min before scopolamine (1.5 mg/kg, i.p.). Data are expressed as mean ± S.E.M. Statistical analysis was performed using One-way ANOVA followed by post-hoc Tukey's test where appropriate, *** p<0.001 vs. controls (Veh); ^# p<0.05, ^## p<0.01 vs. scopolamine-treated animals (Scop).

Figure 2. MQ rescues scopolamine-induced episodic memory impairment.

Effect of MQ treatment in the novel object recognition (A) and passive avoidance (B) tasks using a scopolamine-induced amnesia model in mice. In both tests, MQ (7 and 15 mg/kg, p.o.) was administered 20 min before scopolamine (1 mg/kg, i.p.) before the first trial only. Data are expressed as mean ± S.E.M. Statistical analysis was performed using One-way ANOVA followed by post-hoc Tukey's test. * p<0.05, *** p<0.001 vs. controls (Veh); ^# p<0.05, ^### p<0.001 vs. scopolamine-treated animals (Scop).

Figure 3. Beneficial effect of MQ on Aβ_1–42 i.c.v. treated animals.

Effect of MQ daily treatments in the spontaneous alternation (A) and passive avoidance task (B) using a Aβ- induced amnesia model in mice. 800 pmol Aβ_1–42 and Aβ_42-1 or their vehicle (PBS) were i.c.v. injected 7 and 8 days before T-maze and passive avoidance, respectively. MQ 15 mg/kg p.o. was administered daily for 2, 4, and 6 days before behavioral testing. Data are expressed as mean ± S.E.M. Statistical analysis was performed using One-way ANOVA followed by post-hoc Tukey's test. * p<0.05, *** p<0.001 vs. controls (PBS and Aβ_42-1); ^# p<0.05, ^## p<0.001 vs. amyloid-injected animals.

Figure 4. Neuroprotective effect of MQ against Aβ_1–42 toxicity in rat neuronal cultures.

Primary neuronal cultures of rat were simultaneously exposed to 1 µM Aβ_1–42 and MQ 0.5 or 1 µM after a 24 h sulforaphane (0.5 or 1 µM) pre-treatment. Whereas both the MQ concentrations partially protected from Aβ_1–42 toxicity following 0.5 µM sulforaphane exposure, the administration of 1 µM MQ after a pre-treatment with 1 µM sulforaphane was fully effective in protecting neuronal cultures from Aβ_1–42-induced neuronal death. Cell viability was assessed using the MTT (A) or LDH (B) assays. Data are expressed as mean ± S.E.M. Statistical analysis was performed using One-way ANOVA followed by Dunnett's multiple comparison test. *** p<0.001 compared with CTR; ^# p<0.05, ^## p<0.01, ^### p<0.001 compared with Aβ_1–42.