State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
CNS Neurosci Ther. 2012 Sep;18(9):737-44. doi: 10.1111/j.1755-5949.2012.00359.x. Epub 2012 Jun 28.
Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases. Iptakalim (Ipt), a novel ATP-sensitive potassium (K-ATP) channel opener, has been demonstrated to play multipotential neuroprotective effects in vivo and in vitro. However, it remains unknown whether Ipt could regulate the adult neurogenesis.
Based on the finding that adult neural stem cells (ANSCs) in hippocampus expressed Kir6.1/SUR1-composed K-ATP channel, Kir6.1 heterozygotic (Kir6.1(+/-) ) mice were used to investigate whether and how Ipt regulates adult hippocampal neurogenesis. We showed that administration of Ipt (10 mg/kg) or fluoxetine (Flx, 10 mg/kg) for 4 weeks significantly increased newborn ANSCs in subgranular zone (SGZ) of Kir6.1(+/+) mice but failed to affect those of Kir6.1(+/-) mice. Meanwhile, ANSCs in Kir6.1(+/-) mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes. We further found that Kir6.1(+/-) mice showed lower level of brain-derived neurotrophic factor (BDNF) in hippocampus compared with Kir6.1(+/+) mice. Furthermore, Ipt increased the levels of BDNF and basic fibroblast growth factor (FGF-2) throughout the hippocampus in Kir6.1(+/+) mice but not in Kir6.1(+/-) mice. Moreover, Ipt and Flx enhanced the phosphorylation of Akt and CREB in the hippocampus of Kir6.1(+/+) mice. Notably, these effects were completely abolished in Kir6.1(+/-) mice.
Our findings demonstrate that Ipt stimulates the adult hippocampal neurogenesis via activation of Akt and CREB signal following the opening of Kir6.1-composed K-ATP channels, which gives us an insight into the therapeutic implication of Ipt in the diseases with adult neurogenesis deficiency, such as major depression.
新出现的证据表明，刺激成人神经发生为中枢神经系统疾病提供了新的策略。伊普他卡林（Ipt）是一种新型的三磷酸腺苷（ATP）敏感性钾（K-ATP）通道开放剂，已被证明在体内和体外具有多种潜在的神经保护作用。然而，目前尚不清楚 Ipt 是否可以调节成人神经发生。
基于在海马体中的成年神经干细胞（ANSCs）中表达 Kir6.1/SUR1 组成的 K-ATP 通道的发现，使用 Kir6.1 杂合子（Kir6.1(+/-)）小鼠来研究 Ipt 是否以及如何调节成年海马神经发生。我们发现，给予 Ipt（10 mg/kg）或氟西汀（Flx，10 mg/kg）4 周可显著增加 Kir6.1(+/+)小鼠的颗粒下区（SGZ）中新的 ANSCs，但对 Kir6.1(+/-)小鼠没有影响。同时，Kir6.1(+/-)小鼠中的 ANSCs存活率降低，分化为星形胶质细胞的能力受损。我们进一步发现，与 Kir6.1(+/+)小鼠相比，Kir6.1(+/-)小鼠的海马体中的脑源性神经营养因子（BDNF）水平较低。此外，Ipt 增加了 Kir6.1(+/+)小鼠整个海马体中 BDNF 和碱性成纤维细胞生长因子（FGF-2）的水平，但在 Kir6.1(+/-)小鼠中没有增加。此外，Ipt 和 Flx 增强了 Kir6.1(+/+)小鼠海马体中 Akt 和 CREB 的磷酸化。值得注意的是，这些作用在 Kir6.1(+/-)小鼠中完全被消除。
我们的研究结果表明，Ipt 通过激活 Akt 和 CREB 信号来刺激成年海马神经发生，这是通过 Kir6.1 组成的 K-ATP 通道的开放来实现的，这为我们提供了一种治疗方法的见解，即在具有成年神经发生缺陷的疾病中，如重度抑郁症，Ipt 的治疗作用。
