title: ISX-9 can potentiate cell proliferation and neuronal commitment in the rat dentate gyrus.
abstract: Adult hippocampal neurogenesis can be modulated by various physiological and pathological conditions, including stress, affective disorders, and several neurological conditions. Given the proposed role of this form of structural plasticity in the functioning of the hippocampus (namely learning and memory and affective behaviors), it is believed that alterations in hippocampal neurogenesis might underlie some of the behavioral deficits associated with these psychiatric and neurological conditions. Thus, the search for compounds that can reverse these deficits with minimal side effects has become a recognized priority. In the present study we tested the pro-neurogenic effects of isoxazole 9 (Isx-9), a small synthetic molecule that has been recently identified through the screening of chemical libraries in stem cell-based assays. We found that administration of Isx-9 for 14days was able to potentiate cell proliferation and increase the number of immature neurons in the hippocampal DG of adult rats. In addition, Isx-9 treatment was able to completely reverse the marked reduction in these initial stages of the neurogenic process observed in vehicle-treated animals (which were submitted to repeated handling and exposure to daily intraperitoneal injections). Based on these results, we recommend that future neurogenesis studies that require repeated handling and manipulation of animals should include a naïve (non-manipulated) control to determine the baseline levels of hippocampal cell proliferation and neuronal differentiation. Overall, these findings demonstrate that Isx-9 is a promising synthetic compound for the mitigation of stress-induced deficits in adult hippocampal neurogenesis. Future studies are thus warranted to evaluate the pro-neurogenic properties of Isx-9 in animal models of affective and neurological disorders associated with impaired hippocampal structural plasticity.
authors.affiliation: Division of Medical Sciences and UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada; Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Luis E B
authors.initials: LE
authors.lastname: Bettio
authors.affiliation: Division of Medical Sciences and UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Anna R
authors.initials: AR
authors.lastname: Patten
authors.affiliation: Division of Medical Sciences and UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Joana
authors.initials: J
authors.lastname: Gil-Mohapel
authors.affiliation: Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Natasha F
authors.initials: NF
authors.lastname: O'Rourke
authors.affiliation: Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Ronan P
authors.initials: RP
authors.lastname: Hanley
authors.affiliation: Division of Medical Sciences and UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Kennedy
authors.affiliation: Division of Medical Sciences and UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada; Department of Biochemistry and Microbiology, University of Victoria, British Columbia, Canada.
authors.forename: Karthik
authors.initials: K
authors.lastname: Gopalakrishnan
authors.affiliation: Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil.
authors.forename: Ana Lúcia S
authors.initials: AL
authors.lastname: Rodrigues
authors.affiliation: Department of Chemistry, University of Victoria, Victoria, British Columbia, Canada.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wulff
authors.affiliation: Division of Medical Sciences and UBC Island Medical Program, University of Victoria, Victoria, British Columbia, Canada. Electronic address: brain64@uvic.ca.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Christie
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D018891:Dentate Gyrus / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D007150:Immunohistochemistry; D007555:Isoxazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D015394:Molecular Structure; D055495:Neurogenesis / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D017207:Rats, Sprague-Dawley; D013315:Stress, Psychological / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D013876:Thiophenes / Q000138:chemical synthesis / Q000494:pharmacology*; D047392:beta-Cyclodextrins / Q000494:pharmacology
chemical_list: D002491:Central Nervous System Agents; D007555:Isoxazoles; C560085:N-cyclopropyl-5-(thiophen-2-yl)isoxazole-3-carboxamide; D013876:Thiophenes; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin; D003345:Corticosterone
keywords: adult hippocampal neurogenesis; cell proliferation; immature neurons; isoxazole 9 (Isx-9); stress