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

研究成果: Article査読

12 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)272-281
ページ数10
ジャーナルNeurochemistry International
108
DOI
出版ステータスPublished - 2017 9

ASJC Scopus subject areas

  • 細胞および分子神経科学
  • 細胞生物学

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