I ptakalim Enhances Adult Mouse Hippocampal Neurogenesis Via Opening K ir6.1‐Composed K‐ATP Channels Expressed in Neural Stem Cells

Summary Background and Purpose Emerging evidence indicates that stimulating adult neurogenesis provides novel strategies for central nervous system diseases. I ptakalim ( I pt), 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 I pt could regulate the adult neurogenesis. Methods and Results Based on the finding that adult neural stem cells ( ANSC s) in hippocampus expressed K ir6.1/ SUR 1‐composed K ‐ ATP channel, K ir6.1 heterozygotic ( K ir6.1 +/− ) mice were used to investigate whether and how I pt regulates adult hippocampal neurogenesis. We showed that administration of I pt (10 mg/kg) or fluoxetine ( F lx, 10 mg/kg) for 4 weeks significantly increased newborn ANSC s in subgranular zone ( SGZ ) of K ir6.1 +/+ mice but failed to affect those of K ir6.1 +/− mice. Meanwhile, ANSC s in K ir6.1 +/− mice exhibited decreased survival rate and impaired ability of differentiation into astrocytes. We further found that K ir6.1 +/− mice showed lower level of brain‐derived neurotrophic factor ( BDNF ) in hippocampus compared with K ir6.1 +/+ mice. Furthermore, I pt increased the levels of BDNF and basic fibroblast growth factor ( FGF ‐2) throughout the hippocampus in K ir6.1 +/+ mice but not in K ir6.1 +/− mice. Moreover, I pt and F lx enhanced the phosphorylation of A kt and CREB in the hippocampus of K ir6.1 +/+ mice. Notably, these effects were completely abolished in K ir6.1 +/− mice. Conclusions Our findings demonstrate that I pt stimulates the adult hippocampal neurogenesis via activation of A kt and CREB signal following the opening of K ir6.1‐composed K ‐ ATP channels, which gives us an insight into the therapeutic implication of I pt in the diseases with adult neurogenesis deficiency, such as major depression.