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

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.

• Authors: Yasushi Yabuki, Xu Jing, Kohji Fukunaga
• Journal: Neurochemistry international (Neurochem Int) Vol. 108 Pg. 272-281 (Sep 2017) ISSN: 1872-9754 [Electronic] England
• PMID: 28457878 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Calcium Channels, T-Type
• Imidazoles
• Neuroprotective Agents
• Nicotinic Agonists
• Receptors, Nicotinic
• SAK3 compound
• Spiro Compounds

Topics

• Animals
• Avoidance Learning (drug effects, physiology)
• Brain Ischemia (metabolism, prevention & control)
• Calcium Channels, T-Type (metabolism)
• Cell Death (drug effects, physiology)
• Cell Survival (drug effects, physiology)
• Dose-Response Relationship, Drug
• Imidazoles (pharmacology, therapeutic use)
• Male
• Mice
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Nicotinic Agonists (pharmacology, therapeutic use)
• Receptors, Nicotinic (metabolism)
• Spiro Compounds (pharmacology, therapeutic use)