AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: Studies in cognitively poor middle-aged mice

• Published in: Behavioural brain research Vol. 286; pp. 97 - 103
• Main Authors: Giménez-Llort, L., Ratia, M., Pérez, B., Camps, P., Muñoz-Torrero, D., Badia, A., Clos, M.V.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-06-2015
• Subjects: Acetylcholinesterase inhibitors; Aging; Aging - drug effects; Aging - psychology; Aminoquinolines - pharmacology; Animals; Anti-Anxiety Agents - pharmacology; Anxiety; Anxiety - drug therapy; Cholinesterase Inhibitors - pharmacology; Chronic treatment; Cognition - drug effects; Cognition Disorders - drug therapy; Cognitive decline; Heterocyclic Compounds, 4 or More Rings - pharmacology; Huprine X; Learning - drug effects; Male; Memory, Long-Term - drug effects; Memory, Short-Term - drug effects; Mice, 129 Strain; Mice, Inbred C57BL; Motor Activity - drug effects; Nootropic Agents - pharmacology; Random Allocation; Visual Perception - drug effects; Cognitive decline; Acetylcholinesterase inhibitors; Aging; Anxiety; Chronic treatment; Huprine X
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2015.02.042

•Chronic treatment with AVCRI104P3 improved cognition-decline in 12-month-old mice.•Cognitive benefits were seen in both short- and long-term learning and memory.•Here, its ‘in vitro’ equipotent dose of Huprine X improved short-term memory and cue-learning.•AVCRI104P3 exerted anxiolytic actions not seen with equipotent Huprine X.•Both drugs elicited benefits in the absence of the adverse side effects of AChEIs.
The present work describes, for the first time, the in vivo effects of the multitarget compound AVCRI104P3, a new anticholinesterasic drug with potent inhibitory effects on human AChE, human BuChE and BACE-1 activities as well as on the AChE-induced and self-induced Aβ aggregation. We characterized the behavioral effects of chronic treatment with AVCRI104P3 (0.6μmolkg−1, i.p., 21 days) in a sample of middle aged (12-month-old) male 129/Sv×C57BL/6 mice with poor cognitive performance, as shown by the slow acquisition curves of saline-treated animals. Besides, a comparative assessment of cognitive and non-cognitive actions was done using its in vitro equipotent doses of huprine X (0.12μmolkg−1), a huperzine A-tacrine hybrid. The screening assessed locomotor activity, anxiety-like behaviors, cognitive function and side effects. The results on the ‘acquisition’ of spatial learning and memory show that AVCRI104P3 exerted pro-cognitive effects improving both short- and long-term processes, resulting in a fast and efficient acquisition of the place task in the Morris water maze. On the other hand, a removal test and a perceptual visual learning task indicated that both AChEIs improved short-term ‘memory’ as compared to saline treated mice. Both drugs elicited the same response in the corner test, but only AVCRI104P3 exhibited anxiolytic-like actions in the dark/light box test. These cognitive-enhancement and anxiolytic-like effects demostrated herein using a sample of middle-aged animals and the lack of adverse effects, strongly encourage further studies on AVCRI104P3 as a promising multitarget therapeutic agent for the treatment of cholinergic dysfunction underlying natural aging and/or dementias.