Background and purpose: 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.
Methods and results: 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.
Conclusions: 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.
© 2012 Blackwell Publishing Ltd.