title: Novel nootropic drug sunifiram improves cognitive deficits via CaM kinase II and protein kinase C activation in olfactory bulbectomized mice.
abstract: Alzheimer's disease (AD) shows degeneration of the cholinergic system in the medial septum, thereby eliciting down-regulation of the olfactory function in patients. We have previously reported that olfactory bulbectomized (OBX) mice show hippocampus-dependent memory impairment as assessed by memory-related behavioral tasks and hippocampal long-term potentiation (LTP). In the present study, we focused whether novel pyrrolidone nootropic drug sunifiram improves both memory impairment and depression observed in OBX mice. OBX mice were administered once a day for 7-12 days with sunifiram (0.01-1.0mg/kg p.o.) from 10 days after operation with or without gavestinel (10mg/kg i.p.), which is glycine-binding site inhibitor of N-methyl-d-aspartate receptor (NMDAR). The spatial reference memory assessed by Y-maze and short-term memory assessed by novel object recognition task were significantly improved by sunifiram treatment in OBX mice. Sunifiram also restored hippocampal LTP injured in OBX mice without treatment with gavestinel. By contrast, sunifiram treatment did not ameliorate the depressive behaviors assessed by tail suspension task in OBX mice. Notably, sunifiram treatment restored CaMKIIα (Thr-286) autophosphorylation and GluR1 (Ser-831) phosphorylation in the hippocampal CA1 region from OBX mice to the levels of control mice. Likewise, sunifiram treatment improved PKCα (Ser-657) autophosphorylation and NR1 (Ser-896) phosphorylation to the control levels. Stimulation of CaMKII and PKC autophosphorylation by sunifiram was significantly inhibited by pre-treatment with gavestinel. However, sunifiram treatment did not affect the phosphorylation of CaMKIV (Thr-196) and ERK. Taken together, sunifiram ameliorates OBX-induced deficits of memory-related behaviors and impaired LTP in the hippocampal CA1 region via stimulation of glycine-binding site of NMDAR.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. shigeki@m.tohoku.ac.jp
authors.forename: Shigeki
authors.initials: S
authors.lastname: Moriguchi
authors.forename: Tomoya
authors.initials: T
authors.lastname: Tanaka
authors.forename: Hideaki
authors.initials: H
authors.lastname: Tagashira
authors.forename: Toshio
authors.initials: T
authors.lastname: Narahashi
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005106:Exploratory Behavior / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D019417:Hindlimb Suspension; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D007211:Indoles / Q000008:administration & dosage; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000187:drug effects; D018697:Nootropic Agents / Q000627:therapeutic use*; D009830:Olfactory Bulb / Q000601:surgery; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D021641:Recognition, Psychology / Q000187:drug effects; D014404:Tubulin / Q000378:metabolism
chemical_list: C105319:3-(2-((phenylamino)carbonyl)ethenyl)-4,6-dichloroindole-2-carboxylic acid; D018691:Excitatory Amino Acid Antagonists; D007211:Indoles; D018697:Nootropic Agents; D010879:Piperazines; D017470:Receptors, Glutamate; D014404:Tubulin; C416655:DM 235; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D048049:Extracellular Signal-Regulated MAP Kinases