Abstract
The behavioural effects of huprine X, a new anticholinesterasic inhibitor, as well as its effects on the regulation of protein kinase C (PKC), mitogen activated protein kinase (MAPK) and alpha-secretase (ADAM10 and TACE/ADAM17) related to amyloid precursor protein (APP) processing remain to be established. In the present work, 12 month old 126/SvxC57b/6 male mice which received chronic i.p. treatment with either saline, huprine X (0.04 micromol kg(-1) or huprine X (0.12 micromol kg(-1), were submitted to a battery of behavioural tests and thereafter the brains were dissected to study the neurochemical effects induced by huprine X. The results show that, in a dose dependent manner, huprine X facilitates learning and memory in the Morris water maze and improves some indicators of emotionality without inducing adverse effects, affecting motor activity nor anxiety-like behaviours, as measured in the open-field and corner tests. Moreover activation of downstream PKC/MAPK signaling pathways may underly these behavioural effects as well as the stimulation of the non-amyloidogenic processing of APP. Results obtained herein using a sample of aged animals strongly suggest that huprine X constitutes a promising therapeutic agent for the treatment of cholinergic dysfunction underlying aging and/or dementias.
Copyright 2010 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ADAM Proteins / metabolism
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ADAM10 Protein
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ADAM17 Protein
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Aging
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Aminoquinolines / administration & dosage
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Aminoquinolines / adverse effects
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Aminoquinolines / pharmacology*
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Aminoquinolines / therapeutic use
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Amyloid Precursor Protein Secretases / metabolism
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Amyloid beta-Protein Precursor / metabolism
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Animals
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Behavior, Animal / drug effects*
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Cholinesterase Inhibitors / administration & dosage
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Cholinesterase Inhibitors / adverse effects
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Cholinesterase Inhibitors / pharmacology*
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Cholinesterase Inhibitors / therapeutic use
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Dose-Response Relationship, Drug
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Heterocyclic Compounds, 4 or More Rings / administration & dosage
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Heterocyclic Compounds, 4 or More Rings / adverse effects
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Heterocyclic Compounds, 4 or More Rings / pharmacology*
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Heterocyclic Compounds, 4 or More Rings / therapeutic use
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Hippocampus / drug effects
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Hippocampus / metabolism
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Learning / drug effects
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Male
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinases / metabolism*
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Motor Activity / drug effects
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Protein Kinase C-alpha / metabolism*
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Protein Transport / drug effects
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Random Allocation
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Signal Transduction / drug effects
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Time Factors
Substances
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Aminoquinolines
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Amyloid beta-Protein Precursor
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Cholinesterase Inhibitors
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Heterocyclic Compounds, 4 or More Rings
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Membrane Proteins
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huprine X
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Prkca protein, mouse
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Protein Kinase C-alpha
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Mitogen-Activated Protein Kinases
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Amyloid Precursor Protein Secretases
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ADAM Proteins
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ADAM10 Protein
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Adam10 protein, mouse
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ADAM17 Protein
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Adam17 protein, mouse