title: Sigma-1 receptor stimulation by dehydroepiandrosterone ameliorates cognitive impairment through activation of CaM kinase II, protein kinase C and extracellular signal-regulated kinase in olfactory bulbectomized mice.
abstract: Dehydroepiandrosterone (DHEA) is one of the most abundant neurosteroids synthesized de novo in the CNS. We here found that sigma-1 receptor stimulation by DHEA improves cognitive function through phosphorylation of synaptic proteins in olfactory bulbectomized (OBX) mouse hippocampus. We have previously reported that calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC) and extracellular signal-regulated kinase (ERK) were impaired in OBX mouse hippocampus. OBX mice were administered once a day for 7-8 days with DHEA (30 or 60 mg/kg p.o.) 10 days after operation. The spatial, cognitive and conditioned fear memories in OBX mice were significantly improved as assessed by Y-maze, novel object recognition and passive avoidance task, respectively. DHEA also improved impaired hippocampal long-term potentiation in OBX mice. Notably, DHEA treatment restored PKCα (Ser-657) autophosphorylation and NR1 (Ser-896) and myristoylated alanine-rich protein kinase C substrate (Ser-152/156) phosphorylation to the control levels in the hippocampal CA1 region. Likewise, DHEA treatment improved CaMKIIα (Thr-286) autophosphorylation and GluR1 (Ser-831) phosphorylation to the control levels in the CA1 region. Furthermore, DHEA treatment improved ERK and cAMP-responsive element-binding protein (Ser-133) phosphorylation to the control levels. Finally, NE-100, sigma-1 receptor antagonist, significantly inhibited the DHEA-induced improvement of memory-related behaviors and CaMKII, PKC and ERK phosphorylation in CA1 region. Taken together, sigma-1 receptor stimulation by DHEA ameliorates OBX-induced impairment in memory-related behaviors and long-term potentiation in the hippocampal CA1 region through activation of CaMKII, PKC and ERK.
authors: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aramaki-Aoba, Sendai, Japan.
authors: Shigeki
authors: S
authors: Moriguchi
authors: Yui
authors: Y
authors: Yamamoto
authors: Tatsuya
authors: T
authors: Ikuno
authors: Kohji
authors: K
authors: Fukunaga
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D003072:Cognition Disorders / Q000188:drug therapy*; D003687:Dehydroepiandrosterone / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D055724:Electrophysiological Phenomena; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D018782:Maze Learning; D008569:Memory Disorders / Q000188:drug therapy / Q000523:psychology; D051379:Mice; D009830:Olfactory Bulb / Q000502:physiology*; D010766:Phosphorylation; D011437:Propylamines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D017480:Receptors, sigma / Q000819:agonists*; D021641:Recognition, Psychology / Q000187:drug effects; D000097605:Sigma-1 Receptor
chemical_list: D000840:Anisoles; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003687:Dehydroepiandrosterone; D048049:Extracellular Signal-Regulated MAP Kinases; D011437:Propylamines; D011493:Protein Kinase C; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride