PMID- 30196018 OWN - NLM STAT- MEDLINE DCOM- 20181106 LR - 20181106 IS - 1347-8648 (Electronic) IS - 1347-8613 (Linking) VI - 137 IP - 4 DP - 2018 Aug TI - T-type calcium channel enhancer SAK3 produces anti-depressant-like effects by promoting adult hippocampal neurogenesis in olfactory bulbectomized mice. PG - 333-341 LID - S1347-8613(18)30120-8 [pii] LID - 10.1016/j.jphs.2018.07.006 [doi] AB - T-type calcium channels are involved in the pathophysiology of epilepsy, pain, and sleep. Recently, we developed a novel spiroimidazopyridine compound, SAK3 (ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate), which enhances T-type calcium channel currents and improves memory deficits in olfactory bulbectomized (OBX) mice. Here, we demonstrated the anti-depressant effects of SAK3 in OBX mice. Chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.) improved depressive-like behaviors in OBX mice. The impaired adult neurogenesis in the hippocampal dentate gyrus (DG) that occurred 4 weeks after OBX administration was significantly restored by chronic SAK3 administration (0.5 or 1.0 mg/kg, p.o.). Additionally, SAK3 (0.5 mg/kg, p.o.) promoted the proliferation and survival of newborn cells in the naive DG. Moreover, SAK3 administration (0.5 mg/kg, p.o.) antagonized the reduction of calcium/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV phosphorylation levels, thereby rescuing the decreased levels of cAMP response element-binding protein (CREB)/brain derived neurotrophic factor (BDNF) signaling in the OBX DG. The effects of SAK3 were completely blocked by the T-type calcium channel selective blocker NNC 55-0396 (12.5 mg/kg, i.p.). Altogether, these results suggest that SAK3 improves depressive-like behaviors by promoting adult neurogenesis via T-type calcium channel stimulation in the hippocampus. CI - Copyright (c) 2018 The Authors. Production and hosting by Elsevier B.V. All rights reserved. FAU - Xu, Jing AU - Xu J AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan. FAU - Yabuki, Yasushi AU - Yabuki Y AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan. FAU - Yu, Mengze AU - Yu M AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan. FAU - Fukunaga, Kohji AU - Fukunaga K AD - Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba Aoba-ku, Sendai 980-8578, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp. LA - eng PT - Journal Article DEP - 20180717 PL - Japan TA - J Pharmacol Sci JT - Journal of pharmacological sciences JID - 101167001 RN - 0 (Antidepressive Agents) RN - 0 (Calcium Channel Agonists) RN - 0 (Calcium Channels, T-Type) RN - 0 (Imidazoles) RN - 0 (SAK3 compound) RN - 0 (Spiro Compounds) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) SB - IM MH - Administration, Ophthalmic MH - Animals MH - *Antidepressive Agents MH - Calcium Channel Agonists/administration & dosage/*pharmacology MH - Calcium Channels, T-Type/*metabolism MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors MH - Cell Proliferation/drug effects MH - Cell Survival/drug effects MH - Dentate Gyrus/*cytology MH - Depression/*drug therapy MH - Hippocampus/*cytology MH - Imidazoles/administration & dosage/*pharmacology MH - Male MH - Mice MH - Neural Stem Cells/drug effects MH - Neurogenesis/*drug effects MH - Olfactory Bulb/*surgery MH - Spiro Compounds/administration & dosage/*pharmacology MH - Stimulation, Chemical OTO - NOTNLM OT - Anti-depressant OT - BDNF OT - Neurogenesis OT - SAK3 OT - T-type calcium channel EDAT- 2018/09/10 06:00 MHDA- 2018/11/07 06:00 CRDT- 2018/09/10 06:00 PHST- 2018/04/04 00:00 [received] PHST- 2018/05/20 00:00 [revised] PHST- 2018/05/24 00:00 [accepted] PHST- 2018/09/10 06:00 [pubmed] PHST- 2018/11/07 06:00 [medline] PHST- 2018/09/10 06:00 [entrez] AID - S1347-8613(18)30120-8 [pii] AID - 10.1016/j.jphs.2018.07.006 [doi] PST - ppublish SO - J Pharmacol Sci. 2018 Aug;137(4):333-341. doi: 10.1016/j.jphs.2018.07.006. Epub 2018 Jul 17.