Received for publication March 16, 2006.
Revised June 13, 2006.
Accepted for publication June 14, 2006.

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. As sodium orthovanadate (SOV), a protein tyrosine phosphatase inhibitor, can up-regulate tyrosine kinase-linked growth factors receptor signaling via the inhibition of tyrosine residue dephosphorylation, it may be capable of enhancing progenitor cell. 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 SOV (12.5 or 25 mM) or BrdU and Saline (control) on days 1-7 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- but not the contralateral SVZ, and not in non-ischemic rats. Double-immunolabeling with BrdU and double cortin (Dcx), a marker of migrating neuroblast, revealed that the density of double positive cells increased significantly in a SOV dose-dependent manner. TUNEL staining suggested that the SOV-induced increase was not due to anti-apoptotic effects. Treatment with SOV also significantly increased the density of cells positive for BrdU and phosphorylated Akt and BrdU and phosphorylated 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 post-ischemic CNS.

Key words: MCA occlusion, adult neurogenesis, progenitor cell, proliferation, sodium orthovanadate, subventricular zone