title: A steroid isolated from the water mold Achlya heterosexualis induces neurogenesis in vitro and in vivo.
abstract: Using 22R-hydroxycholesterol as a sub-structure to screen natural compound databases, we identified a naturally occurring steroid (sc-7) with a 16-acetoxy-22R-hydroxycholesterol moiety, in which the hydroxyl groups in positions 3 and 22 are esterified by an acetoxy group and in which the carbon in position 26 carries a functional diacetylamino. sc-7 is an analog of the sex steroids dehydro-oogoniol and antheridiol, can be isolated from the water mold Achlya heterosexualis, and promoted neurogenesis in vitro and in vivo. Mouse embryonic teratocarcinoma P19 cells exposed to sc-7 for 2days followed by a 5-day wash-out differentiated into cholinergic neurons that expressed specific neuronal markers and displayed axonal formation. Axons continued growing up to 28days after treatment. In vivo, infusion of sc-7 for 2weeks into the left ventricle of the rat brain followed by a 3-week wash-out induced bromodeoxyuridine uptake by cells of the ependymal layer and subventricular zone that co-localized with doublecortin and glial fibrillary acidic protein immunostaining, demonstrating induction of proliferation and differentiation of neuronal progenitors. Migrating neuroblasts were also observed in the corpus callosum. Thus, under these experimental conditions, adult ependymal cells resumed proliferation and differentiation. Taken together, these results suggest that sc-7 is an interesting molecule for stimulating in situ neurogenesis from resident neuronal progenitors as part of neuron replacement therapy. sc-7 did not bind to nuclear steroid receptors and was not metabolized as a steroid, supporting our hypothesis that the neurogenic effect of sc-7 is not likely due to a steroid-like effect.
authors.affiliation: The Research Institute of the McGill University Health Centre, Montreal, QC, Canada. laurent.lecanu@mcgill.ca
authors.forename: Laurent
authors.initials: L
authors.lastname: Lecanu
authors.forename: Areej I
authors.initials: AI
authors.lastname: Hashim
authors.forename: Althea
authors.initials: A
authors.lastname: McCourty
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D044743:Achlya / Q000737:chemistry*; D000818:Animals; D001369:Axons / Q000187:drug effects; D015415:Biomarkers / Q000737:chemistry; D001973:Bromodeoxyuridine / Q000737:chemistry; D002465:Cell Movement; D049109:Cell Proliferation; D059329:Cholinergic Neurons / Q000737:chemistry / Q000187:drug effects*; D003337:Corpus Callosum / Q000737:chemistry / Q000187:drug effects; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D004805:Ependyma / Q000737:chemistry / Q000187:drug effects; D005904:Glial Fibrillary Acidic Protein / Q000737:chemistry; D006888:Hydroxycholesterols / Q000737:chemistry; D007150:Immunohistochemistry; D057967:Infusions, Intraventricular; D008297:Male; D051379:Mice; D008869:Microtubule-Associated Proteins / Q000737:chemistry; D058953:Neural Stem Cells / Q000737:chemistry / Q000187:drug effects; D055495:Neurogenesis; D009479:Neuropeptides / Q000737:chemistry; D051381:Rats; D020318:Rats, Long-Evans; D013256:Steroids / Q000737:chemistry* / Q000302:isolation & purification; D018243:Teratocarcinoma / Q000188:drug therapy; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry; D014746:Vimentin / Q000737:chemistry
chemical_list: D015415:Biomarkers; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005904:Glial Fibrillary Acidic Protein; D006888:Hydroxycholesterols; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D013256:Steroids; D014404:Tubulin; D014746:Vimentin; C462941:beta3 tubulin, mouse; C003585:22-hydroxycholesterol; D001973:Bromodeoxyuridine