title: Iptakalim enhances adult mouse hippocampal neurogenesis via opening Kir6.1-composed K-ATP channels expressed in neural stem cells.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, China.
authors: Jing-Zhe
authors: JZ
authors: Yang
authors: Xu
authors: X
authors: Huang
authors: Fang-Fang
authors: FF
authors: Zhao
authors: Qiang
authors: Q
authors: Xu
authors: Gang
authors: G
authors: Hu
mesh_terms: D053687:Adult Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D054086:KATP Channels / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D008297:Male; D016555:Matched-Pair Analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology*
chemical_list: D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D018696:Neuroprotective Agents; D011437:Propylamines; C092520:uK-ATP-1 potassium channel