SAK3-Induced neuroprotection is mediated by nicotinic acetylcholine receptors

Koji Fukunaga, Yasushi Yabuki

Research output: Chapter in Book/Report/Conference proceedingChapter

4 Citations (Scopus)


Cholinergic neurotransmission plays a critical role in neuronal plasticity and cell survival in the central nervous system (CNS). Two types of acetylcholine receptors (AChRs), muscarinic AChRs (mAChRs) and nicotinic AChRs (nAChRs), trigger intracellular signaling through G protein activity and ion influx, respectively. To assess mechanisms underlying neuroprotection through nAChRs, we developed SAK3, a novel modulator of nAChR activity. Recently, we found that SAK3 enhances T-type calcium channel activity, promoting ACh release in the hippocampal CA1 region of olfactory-bulbectomized mice. Here, we observed potent SAK3 neuroprotective activity in mice with 20-min bilateral common carotid artery occlusion (BCCAO) or hypothyroidism. Treatment of mice with the α7 nAChR-selective inhibitor methyllycaconitine (0.5 mg/kg/day, p.o.) antagonized SAK3-mediated neuroprotection and memory improvement in BCCAO mice. Single administration of the anti-Graves' disease therapeutic methimazole (MMI) to female mice disrupted olfactory bulb (OB) glomerular structure, and cholinergic neurons largely disappeared in the medial septum followed by memory loss. Chronic SAK3 (0.5-1 mg/kg, p.o.) administration significantly rescued the number of cholinergic medial septum neurons in MMI-treated mice and improved cognitive deficits seen in those mice. Overall, our study suggests that, in mice, the novel nAChR modulator SAK3 can rescue neurons impaired by transient ischemia and hypothyroidism. We also address mechanisms common to SAK3-induced neuroprotection in both conditions.

Original languageEnglish
Title of host publicationNicotinic Acetylcholine Receptor Signaling in Neuroprotection
PublisherSpringer Singapore
Number of pages13
ISBN (Electronic)9789811084881
ISBN (Print)9789811084874
Publication statusPublished - 2018 Apr 4


  • Alzheimer's disease
  • Hypothyroidism
  • Ischemia
  • Memory
  • Methimazole
  • Neuroprotection
  • Nicotinic acetylcholine receptor
  • T-type calcium channel

ASJC Scopus subject areas

  • Medicine(all)
  • Neuroscience(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)


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