title: S 38093, a histamine H3antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice.
abstract: Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer's disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent "context discrimination (CS) test" in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits.
authors.affiliation: CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Guilloux
authors.affiliation: Behavioral and Systems Neuroscience Area, Department of Psychology, Rutgers The State University of New Jersey, Piscataway, NJ, USA.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Samuels
authors.affiliation: CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Indira
authors.initials: I
authors.lastname: Mendez-David
authors.affiliation: Departments of Neuroscience and Psychiatry, Columbia University, New York, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Hu
authors.affiliation: Departments of Neuroscience and Psychiatry, Columbia University, New York, USA.
authors.forename: Marjorie
authors.initials: M
authors.lastname: Levinstein
authors.affiliation: CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Faye
authors.affiliation: CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Maryam
authors.initials: M
authors.lastname: Mekiri
authors.affiliation: Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Suresnes, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mocaer
authors.affiliation: CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Alain M
authors.initials: AM
authors.lastname: Gardier
authors.affiliation: Departments of Neuroscience and Psychiatry, Columbia University, New York, USA.|Department of Integrative Neuroscience, New York State Psychiatric Institute, New York, USA.
authors.forename: René
authors.initials: R
authors.lastname: Hen
authors.affiliation: Pôle d'Innovation Thérapeutique Neuropsychiatrie Servier, Suresnes, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Sors
authors.affiliation: CESP/UMR-S1178, Univ. Paris-Sud, Fac. Pharmacie, INSERM, Université Paris-Saclay, Chatenay-Malabry, France.
authors.forename: Denis J
authors.initials: DJ
authors.lastname: David
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology; D000818:Animals; D053961:Azabicyclo Compounds / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D001549:Benzamides / Q000494:pharmacology*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D018891:Dentate Gyrus / Q000378:metabolism; D004195:Disease Models, Animal; D054314:Drug Inverse Agonism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054828:Histamine H3 Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D053961:Azabicyclo Compounds; D001549:Benzamides; D019208:Brain-Derived Neurotrophic Factor; D054828:Histamine H3 Antagonists; C000624696:S 38093; D042461:Vascular Endothelial Growth Factor A