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P4‐014: SAK3, an T‐Type Ca 2+ Channel Stimulator Inhibits Amyloid Beta Accumulation
Author(s) -
Fukunaga Kohji,
Shinoda Yasuharu,
Izumi Hisanao,
Yabuki Yasushi
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.2103
Subject(s) - hippocampal formation , donepezil , hippocampus , glutamate receptor , pharmacology , amyloid beta , in vivo , neuroscience , cognitive decline , medicine , chemistry , endocrinology , disease , psychology , dementia , biology , receptor , microbiology and biotechnology
Background:We recently developed a novel cognitive enhancer of an Alzheimer disease (AD) therapeutic candidate ST101 (Phase II in USA) which stimulates T-type voltage-gated Ca channels (T-VGCC) (Moriguchi et al., J Neurochem 2012;121:44-53). In Phase II trial, ST101 by combination is donepezil is significantly improved cognition in AD patients. Methods:We here introduced another spiroimidazopyridine derivatives (SAK compounds) (PCT/JP2013/051388), which are much stronger than ST101 when assessed by Ca conductance of T-VGCC with neuronal cells transfected Cav3.1 gene. We evaluated its cognitive improvement and its inhibition of amyloid beta (1-42) accumulation in AD model (APP23) mice. Results: SAK3 treatment significantly enhanced mouse hippocampal LTP. Likewise, SAK3 administration in vivo enhanced the hippocampal glutamate release in mouse hippocampus. The SAK3-induced glutamate release was inhibited by treatment with T-VGCC inhibitor. Consistent with these observations, SAK3 improved cognition in novel objective recognition task in APP23 mice. We also confirmed that the cognitive impairment in AD model mice is improved by 2-3 month treatment with SAK3 (05.mg/kg). The prolonged administration of SAK3 also suppressed the amyloid beta (1-42) accumulation in ADmodel mice. Conclusions: Taken together, the novel T-VGCC stimulator SAK3 elicits the enhancement of glutamate release in the hippocampus, thereby likely improving cognitive impairment in AD mice. We are looking for a partner company to conduct the preclinical studies to develop SAK3 as novel AD therapeutics.