title: Anti-amnesic effect of neurosteroid PREGS in Aβ25-35-injected mice through σ1 receptor- and α7nAChR-mediated neuroprotection.
abstract: A single intracerebroventricular injection of β-amyloid 25-35 peptide (Aβ(25-35)) (9 nmol/mouse) induces the spatial cognitive deterioration and approximately 50% loss of pyramidal cells in hippocampal CA1 region within 1 week. The present study focused on exploring the effects of neurosteroid pregnenolone sulfate (PREGS), in comparison with the selective agonists of sigma-1 receptor (σ(1)R) and α7 nicotinic acetylcholine receptor (α7nAChR), on the cognitive deficits and the death of pyramidal cells in Aβ(25-35)-mice. Herein, we reported that the administration of PREGS (1-100 mg/kg) for 7 days after Aβ(25-35)-injection could dose-dependently ameliorate the cognitive deficits and attenuate the apoptosis of pyramidal cells. Either the σ(1)R antagonist NE100 or the α7nAChR antagonist MLA could block the neuroprotection of PREGS in Aβ(25-35)-mice. Both the σ(1)R agonist PRE084 and the α7nAChR agonist DMXB could mimic the PREGS-neuroprotection against the Aβ(25-35)-neurotoxicity. The neuroprotection of PRE084 was attenuated by MLA, but the DMXB-action was insensitive to NE100. The neuroprotection of PREGS, PRE084 or DMXB was blocked by the phosphatidylinositol-3-kinase (PI3K) inhibitor LY294002, whereas only the effect of PREGS or PRE084 was sensitive to the MAPK/ERK kinase (MEK) inhibitor U0126. PREGS prevented Aβ(25-35)-inhibited Akt (Serine/threonine kinase) phosphorylation leading to increase in caspase-3 activity, which was σ(1)R- and α7nAChR-dependent. By contrast, PREGS-rescued reduction of extracellular signal-related kinase-2 (ERK2) phosphorylation in Aβ(25-35)-mice only required the activation of σ(1)R. Blockage of PREGS-neuroprotection by LY294002 significantly attenuated its anti-amnesic effect in Aβ(25-35)-mice. The findings indicate that the anti-amnesic effects of PREGS in Aβ(25-35)-mice depend on the σ(1)R- and α7nAChR-mediated neuroprotection.
authors.affiliation: Department of Physiology, Nanjing Medical University, Nanjing 210029, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Yang
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Haofei
authors.initials: H
authors.lastname: Wang
authors.forename: Bingzhong
authors.initials: B
authors.lastname: Xu
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tomimoto
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
mesh_terms: D000647:Amnesia / Q000139:chemically induced* / Q000188:drug therapy*; D016229:Amyloid beta-Peptides; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D056547:CA1 Region, Hippocampal / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011284:Pregnenolone / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011978:Receptors, Nicotinic / Q000187:drug effects*; D017480:Receptors, sigma / Q000819:agonists / Q000187:drug effects*; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000097605:Sigma-1 Receptor
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011284:Pregnenolone; D051057:Proto-Oncogene Proteins c-akt; D011978:Receptors, Nicotinic; D017480:Receptors, sigma; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000097605:Sigma-1 Receptor; C579166:Chrna7 protein, mouse; C074636:amyloid beta-protein (25-35); C018370:pregnenolone sulfate