Drug discovery study of Alzheimer's disease target for T-type calcium channel activation

2014 Fiscal Year Final Research Report

• Project/Area Number: 24590653
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Applied pharmacology
• Research Institution: Tohoku University
• Principal Investigator: MORIGUCHI Shigeki 東北大学, 薬学研究科(研究院), 講師 (70374949)
• Co-Investigator(Kenkyū-buntansha): 福永 浩司 東北大学, 大学院薬学研究科, 教授 (90136721)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: ST101 / T-type CGCCs / CaMKII / OBX mice

Outline of Final Research Achievements

We developed a novel cognitive enhancer, ST101 that activates T-type voltage-gated calcium channels (VGCCs). Here, we address whether T-type VGCC activation with ST101 mediates its cognitive effects in vivo and the relevance of T-type VGCC activation to acetylcholine release in the hippocampus. Acute administration of ST101 at 1 mg/kg, i.p. improved memory-related behaviors in olfactory bulbectomized (OBX) mice. Effects of ST101 administration were abolished by pre-administration of the T-type VGCC inhibitor mibefradil. As expected, significantly reduced CaMKIIα, PKCα, and ERK phosphorylation was restored by acute ST101 administration in the OBX mouse hippocampal CA1 region. Enhancement of CaMKIIα and PKCα but not ERK phosphorylation was inhibited by mibefradil. Taken together, stimulation of T-type VGCCs is critical for the enhanced hippocampal ACh release and improved cognitive function seen following ST101 administration.

Free Research Field

薬理学、電気生理学