The T-type calcium channel enhancer SAK3 inhibits neuronal death following transient brain ischemia via nicotinic acetylcholine receptor stimulation

Yasushi Yabuki, Xu Jing, Kohji Fukunaga

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The T-type calcium channel enhancer SAK3 (ethyl 8'-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridin]-2-ene-3-carboxylate) promotes acetylcholine (ACh) release in mouse hippocampus, enhancing cognitive function. Here, we tested SAK3 neuroprotective activity in the context of transient brain ischemia using a 20-min bilateral common carotid arteries occlusion (BCCAO) mouse model. Mice were administered with SAK3 (0.1, 0.5 or 1.0 mg/kg, p.o.) 24 h after BCCAO ischemia. Oral SAK3 (0.5 or 1.0 mg/kg/day, p.o.) administration significantly blocked loss of hippocampal CA1 neurons and memory deficits seen in BCCAO mice. Treatment with α7 nicotinic ACh receptor (nAChR)-selective inhibitor methyllycaconitine (MLA: 6.0 mg/kg/day, i.p.) significantly antagonized both neuroprotection and improvement in memory promoted by SAK3 (0.5 mg/kg/day, p.o.). Acute SAK3 (0.5 mg/kg, p.o.) administration significantly enhanced protein kinase B (Akt) phosphorylation levels in CA1 of control and BCCAO mice. Importantly, treatment of control and BCCAO mice with the non-selective nAChR antagonist mecamylamine (MEC: 1.0 mg/kg, i.p.) or the α7-selective nAChR antagonist MLA (6.0 mg/kg, i.p.), but not the M1 muscarinic ACh receptor (mAChR) antagonist pirenzepine (PZ: 10 mg/kg, i.p.), blocked enhanced Akt activity elicited by SAK3 (0.5 mg/kg, p.o.). We also confirmed that decreased phosphorylated Akt immunoreactivities were rescued by SAK3 (0.5 mg/kg, p.o.) administration in NeuN-positive CA1 neurons of BCCAO mice, an effect blocked by MLA (6.0 mg/kg, i.p.). Finally, we observed α7 nAChR and phosphorylated Akt expression in CA1 pyramidal neurons. We conclude that the T-type calcium channel enhancer SAK3 is neuroprotective in the context of brain ischemia by stimulating nicotinic cholinergic neurotransmission.

Original languageEnglish
Pages (from-to)272-281
Number of pages10
JournalNeurochemistry International
Volume108
DOIs
Publication statusPublished - 2017 Sep

Keywords

  • Akt
  • Bilateral common carotid artery occlusion
  • Neuroprotection
  • Nicotinic acetylcholine receptor
  • SAK3

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology

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