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.
Highlights
Alzheimer’s disease (AD) is a neurological disorder characterized by a progressive loss of cognitive function, dementia and altered behavior
Animals receiving vehicle focused their search in the appropriate area, while scopolamine-treated mice (1.5 mg/kg, i.p.) showed a significant decrease in the time spent in the correct region of the pool (p,0.001 vs. control animals)
In the present study, combining the scopolamine- and Abinduced amnesia models with various behavioral tasks, we investigated the efficacy of MQ in treating cognitive dysfunction
Summary
Alzheimer’s disease (AD) is a neurological disorder characterized by a progressive loss of cognitive function, dementia and altered behavior. Based on the ‘‘cholinergic hypothesis’’ of AD [2], several classes of acetylcholinesterase (AChE) inhibitors have been identified [3], leading eventually to the discovery of galantamine, donepezil, and rivastigmine These are the only available drugs for the treatment of AD, apart from memantine, a noncompetitive N-methyl-Daspartate receptor antagonist. A more recent hypothesis (‘‘amyloid hypothesis’’) states that a possible cause of AD is the altered production, aggregation, and deposition of beta-amyloid peptide (Ab), which results in the formation of Ab fibrils and plaques [4]. Based on this idea, remarkable efforts have been devoted to the search for disease-modifying drugs. Possible interactions between Ab, oxidative stress, and tangles have been proposed, making the pathogenesis of this disease extremely complex [11]
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