DMXB (GTS-21) ameliorates the cognitive deficits in beta amyloid(25-35(-) ) injected mice through preventing the dysfunction of alpha7 nicotinic receptor.
Intracerebroventricular injection of beta-amyloid(25-35) (Abeta(25-35)) in mice leads to cognitive deficits with the dysfunction of alpha7 nicotinic acetylcholine receptor (alpha7nAChR) within 1-2 weeks in a dose-dependent manner. The present study focused on the effect of DMXB, a selective alpha7nAChR agonist, on Abeta(25-35) (3 nmol)-impaired spatial memory and alpha7nAChR function. We found that the treatment with DMXB on days 1-10 after Abeta(25-35) injection dose-dependently prevented Abeta(25-35)-induced impairment of acquisition performance and probe trail test in Morris water maze. Importantly, the treatment with DMXB (1 mg/kg) perfectly prevented Abeta(25-35)-induced depression of alpha7nAChR response, which was associated with improving the probability of presynaptic glutamate release and the induction of high-frequency stimulation (HFS)-dependent long-term potentiation (LTP) in hippocampal Schaffer collaterale-CA1 synapse. Furthermore, although either the basal level of extracellular signal-regulated kinase 2 (ERK2) or its phosphorylation in the hippocampus had no difference between control and Abeta(25-35) mice, the Abeta(25-35) injection significantly attenuated HFS-triggered increase in ERK2 phosphorylation. The treatment with DMXB also rescued the ERK2 phosphorylation triggered by HFS in Abeta(25-35) mice that is required for LTP induction. This study firstly provides in vivo evidence that the anti-amnesic effect of DMXB is likely due to preventing the Abeta(25-35)-induced dysfunction of alpha7nAChR.
Chen
Lei
L
Department of Physiology, Nanjing Medical University, Nanjing, China.
Wang
Haofei
H
Zhang
Zhuo
Z
Li
Zhen
Z
He
Danjun
D
Sokabe
Masahiro
M
Chen
Ling
L
D016229:Amyloid beta-Peptides; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001597:Benzylidene Compounds / Q000627:therapeutic use*; D003072:Cognition Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005071:Evoked Potentials / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D010446:Peptide Fragments; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000627:therapeutic use*; D011930:Reaction Time / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism*; D013028:Space Perception / Q000187:drug effects; D064569:alpha7 Nicotinic Acetylcholine Receptor
D016229:Amyloid beta-Peptides; D001597:Benzylidene Compounds; C579166:Chrna7 protein, mouse; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D011725:Pyridines; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C074636:amyloid beta-protein (25-35); C088936:3-(2,4-dimethoxybenzylidene)anabaseine; D019950:Mitogen-Activated Protein Kinase 1