Program

PO2-1-26

Preclinical studies of T-type calcium channel enhancer in Alzheimer's disease therapy

[Speaker] Kohji Fukunaga:1
[Co-author] Hisanao Izumi:1, Yasuharu Shinoda:1, Yasushi Yabuki:1
1:Pharmacology, Tohoku University Graduate School of Pharmaceutical Sciences, Japan

[Background] As Alzheimer disease therapeutics candidate, we have developed SAK3 (US9,173,878 B2). SAK3 stimulates T-type voltage-gated (T-type) calcium channels in Cav3.1 and Cav3.3 transfected neuronal cells (1, 2). We here tested whether SAK3 reduce amyloid beta (1-42) accumulation in Alzheimer model (APP23) mice and confirmed reasonable pharmacokinetics in rat serum and brain after administration with its therapeutic doses. In the present study, we defined whether SAK3 improves cognitive functions and inhibits amyloid beta accumulation in APP transgenic mice. We also carried out pharmacokinetics to determine the relationship between the systemic exposure of SAK3 and its toxicity in rats and dogs by GLP levels.
[Methods] APP23 mice aged 6 and 9 months were treated for two or three months with SAK3 (0.5mg/kg, p.o.) and measured amyloid beta (1-42) levels in both soluble and insoluble fractions from APP23 mouse cortex. We also carried out off-target assay to verify its target molecules for elucidate the reduction of amyloid beta accumulation.
[Results] Chronic administration significantly reduced amyloid beta (1-42) levels in APP23 cortex. Consistent with the reduced amyloid beta (1-42) levels, the numbers of amyloid plaques in the cortex assessed by thioflavin staining were significantly reduced by chronic SAK3 treatment. Furthermore, the cognition assessed by novel object recognition task was improved by chronic administration in APP23 mice. In addition, off-target assay revealed that none of the receptors or channels except for T-type calcium channels interacted with SAK3.
[Conclusion] Taken together, AD therapeutic candidate SAK3 has attractive potentials to reduce amyloid beta accumulation and to improve cognition in AD model mice. This work is supported by Project of Translational and Clinical Research Core Centers from AMED, Japan. The authors declare no conflict of interests.
[References] (1) Yabuki Y, Fukunaga K et al, Neuropharmacology 2017;117:1-13.
(2) Noreen H, Fukunaga K et al, Neurochem Int. 2017;108:91-99.

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