AVCRI104P3, a novel multitarget compound with cognition-enhancing and anxiolytic activities: studies in cognitively poor middle-aged mice.
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 (0.6 μmol kg(-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 (0.12 μmol kg(-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.
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain; Departament de Psiquiatria i Medicina Legal, Universitat Autònoma de Barcelona, Spain. Electronic address: lidia.gimenez@uab.cat.
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Giménez-Llort
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain; Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Spain.
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Ratia
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain; Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Spain.
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Pérez
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Spain.
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Camps
Laboratori de Química Farmacèutica (Unitat Associada al CSIC), Facultat de Farmàcia, and Institut de Biomedicina (IBUB), Universitat de Barcelona, Spain.
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Muñoz-Torrero
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain; Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Spain.
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Badia
Institut de Neurociències, Universitat Autònoma de Barcelona, Spain; Departament de Farmacologia, de Terapèutica i de Toxicologia, Universitat Autònoma de Barcelona, Spain.
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D000375:Aging / Q000187:drug effects* / Q000523:psychology*; D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001007:Anxiety / Q000188:drug therapy; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007858:Learning / Q000187:drug effects; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D008570:Memory, Short-Term / Q000187:drug effects; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D018697:Nootropic Agents / Q000494:pharmacology*; D011897:Random Allocation; D014796:Visual Perception / Q000187:drug effects
C000603053:AVCRI104P4; D000634:Aminoquinolines; D014151:Anti-Anxiety Agents; D002800:Cholinesterase Inhibitors; D006576:Heterocyclic Compounds, 4 or More Rings; D018697:Nootropic Agents; C404518:huprine X
Acetylcholinesterase inhibitors; Aging; Anxiety; Chronic treatment; Cognitive decline; Huprine X