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Preclinical studies of T-type calcium channel enhancer in Alzheimer’s disease therapy
Kohji Fukunaga, Hisanao Izumi, Yasuharu Shinoda, Yasushi Yabuki
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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. We here tested whether SAK3 reduced amyliod beta (1-42) accumulation in Alzheimer model (APP23) mice and confirmed reasonable pharmacokinetics in rat serum and brain after administration with its therapeutic doses. APP23 mice aged 6 and 9 months were treated for two or three months with SAK3 (0.5mg/kg, p.o.) and measured amyliod beta (1-42) levels in both soluble and insoluble fractions from APP23 mouse cortex. Chronic administration significantly reduced amyliod beta (1-42) levels in APP23 cortex. Consistent with the reduced amyliod beta (1-42) levels, the numbers of amyloid plaques assessed by thioflavin staining were significantly reduced by chronic SAK3 treatment. Furthermore, the cognition assessed by novel object recognition task was improved by the chronic administration. 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.
Research Career:
1980-1988: Instructor in Pharmacology, Kumamoto University Medical School
1988-1990: Research fellow in Molecular Physiology and Howard Hughes Medical Institute, Vanderbilt University (Prof. TR. Soderling laboratory).
1990: Senior Assistant Professor in Pharmacology, Kumamoto University Medical School
1993: Associate Professor in Pharmacology, Kumamoto University Medical School
2002-present: Chairman and Professor in Department of Pharmacology, Graduate School of Pharmaceutical Sciences Tohoku University
2012-present: Visiting Professor in Zhejiang University and Soochow University
References:
Shioda N and Fukunaga K et al., Endocytosis following dopamine D2 receptor activation in critical for neuronal activity and dendritic spine formation via Rabex5/PDGFRb signaling in striatopallidal medium spiny neurons. Mol Psychiatry 2016 doi:10.1038/mp2016.200.
Moriguchi S and Fukunaga K et al., Blockade of KATP channel Kir 6.2 by memantine represents a novel mechanism relevant to Alzheimer’s disease therapy. Mol Psychiatry 2016 doi:10.1038/mp2016.187.