title: Sodium orthovanadate enhances proliferation of progenitor cells in the adult rat subventricular zone after focal cerebral ischemia.
abstract: Neuronal progenitor cells able to produce new neuron and glia persist in the adult central nervous system (CNS). Their proliferation is up-regulated by growth factors or cytokines under some pathological conditions, including ischemia. Because sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor, can up-regulate tyrosine kinase-linked growth factor receptor signaling via the inhibition of tyrosine residue dephosphorylation, it may be capable of enhancing progenitor cells. To investigate the effect of SOV on progenitor cells in the subventricular zone (SVZ), we injected rats intraperitoneally with 50 mg/kg bromodeoxyuridine (BrdU) and 12.5 or 25 mM SOV or BrdU and saline (control) on days 1 to 7 after middle cerebral artery occlusion. The density of BrdU-positive cells in the ipsilateral SVZ showed a significant SOV dose-dependent increase. This effect was found only in the ipsilateral and not contralateral SVZ, and it was not found in nonischemic rats. Double immunolabeling with BrdU and double cortin, a marker of migrating neuroblast, revealed that the density of double-positive cells increased significantly in an SOV dose-dependent manner. Terminal deoxynucleotidyl transferase dUTP nick-end labeling staining suggested that the SOV-induced increase was not due to antiapoptotic effects. Treatment with SOV also significantly increased the density of cells positive for BrdU and phosphorylated Akt and BrdU and phosphorylated extracellular signal-regulated kinase (ERK). We postulate that ischemia triggers off the proliferation of SVZ cells by bioactive factors such as growth factors and that SOV enhances the proliferation of only triggered-off SVZ cells with Akt and ERK activation. Our findings suggest that SOV may aid in the self-repair of the postischemic CNS.
authors.affiliation: Department of Neurosurgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Matsumoto
authors.forename: Motohiro
authors.initials: M
authors.lastname: Morioka
authors.forename: Yu
authors.initials: Y
authors.lastname: Hasegawa
authors.forename: Takayuki
authors.initials: T
authors.lastname: Kawano
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yoshinaga
authors.forename: Tatsumi
authors.initials: T
authors.lastname: Maeda
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Yano
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kai
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Kuratsu
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D002545:Brain Ischemia / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000032:analysis; D008297:Male; D051057:Proto-Oncogene Proteins c-akt / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013234:Stem Cells / Q000187:drug effects*; D014638:Vanadates / Q000494:pharmacology*
chemical_list: D014638:Vanadates; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D001973:Bromodeoxyuridine