Matsumoto Jun, Morioka Motohiro, Hasegawa Yu, Kawano Takayuki, Yoshinaga Yutaka, Maeda Tatsumi, Yano Shigetoshi, Kai Yutaka, Fukunaga Kohji, Kuratsu Jun-ichi
Department of Neurosurgery, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto 860-8556, Japan.
J Pharmacol Exp Ther. 2006 Sep;318(3):982-91. doi: 10.1124/jpet.106.104562. Epub 2006 Jun 16.
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.
能够产生新的神经元和神经胶质细胞的神经祖细胞在成体中枢神经系统（CNS）中持续存在。在包括缺血在内的一些病理条件下，它们的增殖会被生长因子或细胞因子上调。由于蛋白酪氨酸磷酸酶抑制剂原钒酸钠（SOV）可通过抑制酪氨酸残基去磷酸化来上调酪氨酸激酶连接的生长因子受体信号传导，所以它可能能够增强祖细胞。为了研究SOV对脑室下区（SVZ）祖细胞的影响，我们在大脑中动脉闭塞后第1至7天给大鼠腹腔注射50 mg/kg溴脱氧尿苷（BrdU）和12.5或25 mM SOV或BrdU和生理盐水（对照）。同侧SVZ中BrdU阳性细胞的密度呈现出显著的SOV剂量依赖性增加。这种效应仅在同侧而非对侧SVZ中发现，并且在非缺血大鼠中未发现。用BrdU和双皮质素（一种迁移神经母细胞的标志物）进行双重免疫标记显示，双阳性细胞的密度以SOV剂量依赖性方式显著增加。末端脱氧核苷酸转移酶dUTP缺口末端标记染色表明，SOV诱导的增加并非由于抗凋亡作用。用SOV处理还显著增加了BrdU和磷酸化Akt以及BrdU和磷酸化细胞外信号调节激酶（ERK）阳性细胞的密度。我们推测，缺血通过生长因子等生物活性因子触发SVZ细胞的增殖，并且SOV通过激活Akt和ERK来增强仅被触发的SVZ细胞的增殖。我们的研究结果表明，SOV可能有助于缺血后CNS的自我修复。
