title: Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation.
abstract: Phenytoin is a widely used antiepileptic drug that induces cell proliferation in several tissues, such as heart, bone, skin, oral mucosa and neural precursors. Some of these effects are mediated via fibroblast growth factor receptor (FGFR) and epidermal growth factor receptor (EGFR). These receptors are strongly expressed in the adult ventricular-subventricular zone (V-SVZ), the main neurogenic niche in the adult brain. The aim of this study was to determine the cell lineage and cell fate of V-SVZ neural progenitors expanded by phenytoin, as well as the effects of this drug on EGFR/FGFR phosphorylation. Male BALB/C mice received 10 mg/kg phenytoin by oral cannula for 30 days. We analysed the proliferation of V-SVZ neural progenitors by immunohistochemistry and western blot. Our findings indicate that phenytoin enhanced twofold the phosphorylation of EGFR and FGFR in the V-SVZ, increased the number of bromodeoxyuridine (BrdU)+/Sox2+ and BrdU+/doublecortin+ cells in the V-SVZ, and expanded the population of Olig2-expressing cells around the lateral ventricles. After phenytoin removal, a large number of BrdU+/Receptor interacting protein (RIP)+ cells were observed in the olfactory bulb. In conclusion, phenytoin enhanced the phosphorylation of FGFR and EGFR, and promoted the expression of neural precursor markers in the V-SVZ. In parallel, the number of oligodendrocytes increased significantly after phenytoin removal.
authors.affiliation: Department of Neuroscience, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco, Mexico.
authors.forename: Alma Y
authors.identifier: http://orcid.org/0000-0001-7979-9086
authors.initials: AY
authors.lastname: Galvez-Contreras
authors.affiliation: Department of Neuroscience, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco, Mexico.
authors.forename: Rocio E
authors.identifier: http://orcid.org/0000-0001-6220-5456
authors.initials: RE
authors.lastname: Gonzalez-Castaneda
authors.affiliation: Laboratory of Neuroscience, Facultad de Psicologia, Universidad de Colima, Av. Universidad 333, Colima, COL, 28040, Mexico.
authors.forename: Tania
authors.initials: T
authors.lastname: Campos-Ordonez
authors.affiliation: Department of Neuroscience, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Jalisco, Mexico.
authors.forename: Sonia
authors.initials: S
authors.lastname: Luquin
authors.affiliation: Laboratory of Neuroscience, Facultad de Psicologia, Universidad de Colima, Av. Universidad 333, Colima, COL, 28040, Mexico.
authors.forename: Oscar
authors.identifier: http://orcid.org/0000-0002-6527-485X
authors.initials: O
authors.lastname: Gonzalez-Perez
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000089622:Doublecortin Domain Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D020547:Lateral Ventricles / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects* / Q000502:physiology; D009479:Neuropeptides / Q000378:metabolism; D009830:Olfactory Bulb / Q000187:drug effects / Q000502:physiology; D009836:Oligodendroglia / Q000187:drug effects* / Q000502:physiology; D010672:Phenytoin / Q000008:administration & dosage*; D010766:Phosphorylation / Q000187:drug effects; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000378:metabolism
chemical_list: D000927:Anticonvulsants; D000089622:Doublecortin Domain Proteins; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D017468:Receptors, Fibroblast Growth Factor; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D010672:Phenytoin; D066246:ErbB Receptors
keywords: BALB/c; Olig2; Sox2; mouse; neural stem cells; oligodendrocyte