title: Dehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation.
abstract: Dehydroepiandrosterone (DHEA) is the most abundant neurosteroid synthesized de novo in the central nervous system. Oral DHEA administration elicits neuroprotection and cognitive improvement, but mechanisms underlying these functions in cerebral ischemia have remained unclear. Since DHEA is the endogenous ligand for the sigma-1 receptor (σ1R), we determined whether oral DHEA administration prevents neuronal cell death and improves cognition via σ1R stimulation in brain ischemia using a 20-min bilateral common carotid artery occlusion (BCCAO) mouse model. Twenty-four hours after BCCAO ischemia, mice were administered DHEA (15 or 30mg/kg p.o.) daily for 11 consecutive days. Memory deficits following brain ischemia were improved by DHEA administration dose-dependently. Accordingly, DHEA administration significantly prevented neuronal cell death in the hippocampal CA1 region in BCCAO mice. Interestingly, DHEA administration rescued decreases in Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation of extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) in the CA1 region. Moreover, DHEA administration significantly ameliorated decreases in adenosine 5'-triphosphate (ATP) levels and decreased σ1R expression levels in CA1 following BCCAO ischemia. Finally, co-treatment of mice with the σ1R antagonist NE-100 (1mg/kg, p.o.) blocked DHEA effects on memory improvement and neuroprotection in ischemic mice. Taken together, DHEA prevents neuronal cell death and activates CaMKII via σ1R stimulation, thereby improving cognitive deficits following brain ischemia.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yabuki
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Hisanao
authors.initials: H
authors.lastname: Izumi
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Tatuya
authors.initials: T
authors.lastname: Ikuno
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Shioda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology*; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002340:Carotid Artery Diseases; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003687:Dehydroepiandrosterone / Q000494:pharmacology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018697:Nootropic Agents / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017480:Receptors, sigma / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000097605:Sigma-1 Receptor
chemical_list: D000255:Adenosine Triphosphate; D000840:Anisoles; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D003687:Dehydroepiandrosterone; D048049:Extracellular Signal-Regulated MAP Kinases; D009292:Narcotic Antagonists; D018696:Neuroprotective Agents; D018697:Nootropic Agents; D011437:Propylamines; D051057:Proto-Oncogene Proteins c-akt; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C083832:N,N-dipropyl-2-(4-methoxy-3-(2-phenylethoxy)phenyl)ethylamine monohydrochloride
keywords: Bilateral common carotid artery occlusion; Ca(2+)/calmodulin-dependent protein kinase II; Dehydroepiandrosterone; Neuroprotection; Sigma-1 receptor