T-type calcium channel enhancer SAK3 produces anti-depressant-like effects by promoting adult hippocampal neurogenesis in olfactory bulbectomized mice

Jing Xu, Yasushi Yabuki, Mengze Yu, Kohji Fukunaga

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

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 naïve 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.

Original languageEnglish
Pages (from-to)333-341
Number of pages9
JournalJournal of Pharmacological Sciences
Volume137
Issue number4
DOIs
Publication statusPublished - 2018 Aug

Keywords

  • Anti-depressant
  • BDNF
  • Neurogenesis
  • SAK3
  • T-type calcium channel

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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