Functional significance of target molecule of cognitive enhancer ST101 and drug development
Project/Area Number |
25293124
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Partial Multi-year Fund |
Section | 一般 |
Research Field |
Applied pharmacology
|
Research Institution | Tohoku University |
Principal Investigator |
Fukunaga Kohji 東北大学, 薬学研究科(研究院), 教授 (90136721)
|
Co-Investigator(Kenkyū-buntansha) |
FUKUDA TAKAICHI 熊本大学, 大学院生命科学研究部, 教授 (50253414)
MORIGUCHI SHIGEKI 東北大学, 大学院薬学研究科, 講師 (70374949)
|
Project Period (FY) |
2013-04-01 – 2016-03-31
|
Project Status |
Completed (Fiscal Year 2015)
|
Budget Amount *help |
¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000)
Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2014: ¥7,280,000 (Direct Cost: ¥5,600,000、Indirect Cost: ¥1,680,000)
Fiscal Year 2013: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
|
Keywords | アルツハイマー病 / T型カルシウムチャネル / アミロイドβ / アセチルコリン / 嗅球摘出マウス / T型カルシウムチャネル / LTP |
Outline of Final Research Achievements |
After structure optimization of ST101 as cognitive enhancer, we developed the novel spiro-imidazopyridine derivative, SAK3. Oral administration of SAK3 (0.5mg/kg) enhanced hippocampal acetylcholine release through T-type calcium channels. In olfactory bulbectomized mice, oral administration of SAK3 improved cognitive function by activation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in the hippocampus. We next treated Alzheimer model mice APP23 with SAK3 (0.5mg/kg) for three months. The SAK3 treatment inhibited amyloid beat protein accumulation, thereby improving cognitive dysfunction. We also established evaluation protocol of pharmacodynamics after oral administration in rats. Overall, we conduct preclinical studies of SAK3 for safety and pharmacodynamic properties.
|
Report
(4 results)
Research Products
(143 results)
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[Journal Article] Valproic acid influences MTNR1A intracellular trafficking and signaling in a β-arrestin 2-dependent manner.2016
Author(s)
Hong LL, Jiang Q, Long S, Wang H, Zhang LD, Tian Y, Wang CK, Cao JJ, Tao RR, Huang JY, Liao MH, Lu YM, Fukunaga K, Zhou NM, Han F.
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Journal Title
Molecular Neurobiology
Volume: 53(2)
Issue: 2
Pages: 1237-1246
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Atg5 deficit exaggerates the lysosome formation and cathepsin B activation in mice brain after lipid nanoparticles injection2014
Author(s)
Lu NN, Liu J, Tian Y, Liao MH, Wang H, Lu YM, Tao RR, Hong LJ, Liu SS, Fukunaga K, Du YZ, Han F
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Journal Title
Nanomedicine
Volume: 10
Issue: 8
Pages: 1843-1852
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] In vivo two-photon fluorescence microscopy reveals disturbed cerebral capillary blood flow and increased susceptibility to ischemic insults in diabetic mice2014
Author(s)
Huang JY, Li LT, Wang H, Liu SS, Lu YM, Liao MH, Tao RR, Hong LJ, Fukunaga K, Chen Z, Wilcox CS, Lai EY, Han F
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Journal Title
CNS Neurosci Ther
Volume: 20
Issue: 9
Pages: 816-822
DOI
Related Report
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Nitrosative stress induces peroxiredoxin 1 ubiquitination during ischemic insult via E6AP activation in endothelial cells both in vitro and in vivo2014
Author(s)
Tao RR, Wang H, Hong LJ, Huang JY, Lu YM, Liao MH, Ye WF, Lu NN, Zhu DY, Huang Q, Fukunaga K, Lou YJ, Shoji I, Wilcox CS, Lai EY, Han F
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Journal Title
Antioxid Redox Signal
Volume: (in press)
Issue: 1
Pages: 1-16
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Melatonin reverses the decreases in hippocampal protein serine/threonine kinases observed in an animal model of autism2014
Author(s)
Tian Y, Yabuki Y, Moriguchi S, Fukunaga K, Mao PJ, Hong LJ, Lu YM, Wang R, Ahmed MM, Liao MH, Huang JY, Zhang RT, Zhou TY, Long S, Han F
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Journal Title
J Pineal Res.
Volume: 56
Issue: 1
Pages: 1-11
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Targeted therapy of brain ischaemia using Fas ligand antibody conjugated PEG-lipid nanoparticles2013
Author(s)
Lu YM, Huang JY, Wang H, Lou XF, Liao MH, Hong LJ, Tao RR, Ahmed MM, Shan CL, Wang XL, Fukunaga K, Du YZ, Han F
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Journal Title
Biomaterials
Volume: 35
Issue: 1
Pages: 530-7
DOI
Related Report
Peer Reviewed
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[Journal Article] The effect of lipid nanoparticle PEGylation on neuroinflammatory response in mouse brain2013
Author(s)
Huang JY, Lu YM, Wang H, Liu J, Liao MH, Hong LJ, Tao RR, Ahmed MM, Liu P, Liu SS, Fukunaga K, Du YZ, Han F
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Journal Title
Biomaterials
Volume: 34
Issue: 32
Pages: 7960-70
DOI
Related Report
Peer Reviewed
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[Journal Article] Interaction of PICK1 with C-Terminus of Growth Hormone–Releasing Hormone Receptor (GHRHR) Modulates Trafficking and Signal Transduction of Human GHRHR2013
Author(s)
Katsushima Y, Sato T., Yamada C., Ito M., Suzuki Y., Ogawa E., Sukegawa I., Sukegawa J., Fukunaga K., Yanagisawa T.
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Journal Title
Journal of Pharmacological Sciences
Volume: 122
Issue: 3
Pages: 193-204
DOI
NAID
ISSN
1347-8613, 1347-8648
Related Report
Peer Reviewed
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[Journal Article] Influence of maternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin on socioemotional behaviors in offspring rats.2013
Author(s)
Nguyen AT, Nishijo M, Hori E, Nguyen NM, Pham TT, Fukunaga K, Nakagawa H, Tran AH, Nishijo H.
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Journal Title
Environ Health Insights
Volume: 7
Pages: 1-14
DOI
Related Report
Peer Reviewed
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[Journal Article] The Disturbance of Hippocampal CaMKII/PKA/PKC Phosphorylation in Early Experimental Diabetes Mellitus.2013
Author(s)
Liao MH, Xiang YC, Huang JY, Tao RR, Tian Y, Ye WF, Zhang GS, Lu YM, Ahmed MM, Liu ZR, Fukunaga K, Han F.
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Journal Title
CNS Neurosci Ther.
Volume: -
Issue: 5
Pages: 329-36
DOI
Related Report
Peer Reviewed
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[Journal Article] The γ-secretase blocker DAPT reduces the permeability of the blood-brain barrier by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia.2013
Author(s)
Zhang GS, Tian Y, Huang JY, Tao RR, Liao MH, Lu YM, Ye WF, Wang R, Fukunaga K, Lou YJ, Han F.
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Journal Title
CNS Neurosci Ther.
Volume: 19(1)
Issue: 1
Pages: 53-60
DOI
Related Report
Peer Reviewed
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[Journal Article] Tao RR, Huang JY, Shao XJ, Ye WF, Tian Y, Liao MH, Fukunaga K, Lou YJ, Han F, Lu YM. Ischemic injury promotes Keap1 nitration and disturbance of antioxidative responses in endothelial cells: a potential vasoprotective effect of melatonin.2013
Author(s)
Tao RR, Huang JY, Shao XJ, Ye WF, Tian Y, Liao MH, Fukunaga K, Lou YJ, Han F, Lu YM.
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Journal Title
J Pineal Res.
Volume: 54(3)
Issue: 3
Pages: 271-281
DOI
Related Report
Peer Reviewed
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