PMID- 24067927 OWN - NLM STAT- MEDLINE DCOM- 20140826 LR - 20211203 IS - 1873-7064 (Electronic) IS - 0028-3908 (Linking) VI - 77 DP - 2014 Feb TI - Staurosporine induces dopaminergic neurite outgrowth through AMP-activated protein kinase/mammalian target of rapamycin signaling pathway. PG - 39-48 LID - S0028-3908(13)00419-X [pii] LID - 10.1016/j.neuropharm.2013.09.012 [doi] AB - Axonal degeneration of dopaminergic neurons is one of the pathological features in the early stages of Parkinson disease. Promotion of axonal outgrowth of the remaining dopaminergic neurons leads to the recovery of the nigrostriatal pathway. Staurosporine (STS), a wide-spectrum kinase inhibitor, induces neurite outgrowth in various cell types, although its mechanism of action remains elusive. In this study, we analyzed which protein kinase is involved in STS-induced neurite outgrowth. We have previously established the method to measure the length of dopaminergic neurites that extend from a mesencephalic cell region, which is formed on a coverslip by an isolation wall. By means of this method, we clarified that STS treatment causes dopaminergic axonal outgrowth in mesencephalic primary cultures. Among the specific protein kinase inhibitors we tested, compound C (C.C), an AMP-activated protein kinase (AMPK) inhibitor, promoted dopaminergic neurite outgrowth. STS as well as C.C elevated the phosphorylation level of 70-kDa ribosomal protein S6 kinase, a downstream target of mammalian target of rapamycin (mTOR) signaling pathway. The STS- and C.C-induced dopaminergic neurite outgrowth was suppressed by rapamycin, an mTOR inhibitor. Furthermore, the application of C.C rescued 1-methyl-4-phenylpyridinium ion (MPP(+))-induced dopaminergic neurite degeneration. These results suggest that STS induces dopaminergic axonal outgrowth through mTOR signaling pathway activation as a consequence of AMPK inhibition. CI - Copyright (c) 2013 Elsevier Ltd. All rights reserved. FAU - Wakita, Seiko AU - Wakita S AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: wakita.seiko.88c@st.kyoto-u.ac.jp. FAU - Izumi, Yasuhiko AU - Izumi Y AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: yizumi@pharm.kyoto-u.ac.jp. FAU - Nakai, Toshie AU - Nakai T AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: nakai.toshie.87w@st.kyoto-u.ac.jp. FAU - Adachi, Kanami AU - Adachi K AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: adachi.kanami.26v@st.kyoto-u.ac.jp. FAU - Takada-Takatori, Yuki AU - Takada-Takatori Y AD - Department of Pharmacology, Faculty of Pharmaceutical Sciences, Doshisha Women's College, 97-1 Minamihokodate, Kodo, Kyotanabe, Kyoto 610-0395, Japan. Electronic address: ytakator@dwc.doshisha.ac.jp. FAU - Kume, Toshiaki AU - Kume T AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: tkume@pharm.kyoto-u.ac.jp. FAU - Akaike, Akinori AU - Akaike A AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Graduate School of Pharmaceutical Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan. Electronic address: aakaike@pharm.kyoto-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20130922 PL - England TA - Neuropharmacology JT - Neuropharmacology JID - 0236217 RN - 0 (Enzyme Inhibitors) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - H88EPA0A3N (Staurosporine) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Animals MH - Dopaminergic Neurons/*drug effects/metabolism MH - Enzyme Inhibitors/*pharmacology MH - Neurites/*drug effects/metabolism MH - Neurogenesis/drug effects MH - PC12 Cells MH - Phosphorylation/drug effects MH - Rats MH - Signal Transduction/drug effects MH - Staurosporine/*pharmacology MH - TOR Serine-Threonine Kinases/*metabolism OTO - NOTNLM OT - 1-Methyl-4-phenylpyridinium ion OT - 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine OT - 70-kDa Ribosomal protein S6 kinase OT - AMP-activated protein kinase OT - AMPK OT - C.C OT - CRMP2 OT - DAB OT - DIV OT - DMEM OT - Dopaminergic neuron OT - Dulbecco's modified Eagle medium OT - EMEM OT - Eagle's minimum essential medium OT - FCS OT - HS OT - JNK OT - MAP2 OT - MPP(+) OT - MPTP OT - Mammalian target of rapamycin OT - Neurite outgrowth OT - PD OT - Parkinson disease OT - STS OT - Staurosporine OT - TH OT - TMRM OT - c-Jun NH2-terminal kinase OT - collapsing response mediator protein 2 OT - compound C OT - days in vitro OT - diaminobenzidine OT - fetal calf serum OT - horse serum OT - mTOR OT - mammalian target of rapamycin OT - microtubule associated protein 2 OT - p70S6K OT - pNF OT - phosphorylated neurofilaments OT - staurosporine OT - tetramethylrhodamine methyl ester OT - tyrosine hydroxylase EDAT- 2013/09/27 06:00 MHDA- 2014/08/27 06:00 CRDT- 2013/09/27 06:00 PHST- 2013/03/14 00:00 [received] PHST- 2013/08/12 00:00 [revised] PHST- 2013/09/09 00:00 [accepted] PHST- 2013/09/27 06:00 [entrez] PHST- 2013/09/27 06:00 [pubmed] PHST- 2014/08/27 06:00 [medline] AID - S0028-3908(13)00419-X [pii] AID - 10.1016/j.neuropharm.2013.09.012 [doi] PST - ppublish SO - Neuropharmacology. 2014 Feb;77:39-48. doi: 10.1016/j.neuropharm.2013.09.012. Epub 2013 Sep 22.