Drug development improving mitochondrial pathology in Amyotrophic lateral sclerosis
| Project/Area Number |
16K14574
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
Neurochemistry/Neuropharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 筋萎縮性側索硬化症 / Sigma-1受容体 / ミトコンドリア / SA4503 / Sigma-1R / 筋萎縮側索硬化症 / 脳・神経 / 神経化学 / 神経薬理学 |
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| Outline of Final Research Achievements |
We have been demonstrated that sigma-1 receptor (E102Q) mutation in amyotrophic lateral sclerosis (ALS) patients triggers mitochondrial injury in neuro2A cells. Sigma-1R(E102Q) is accumulated in the mitochondria and reduces ATP production. We here investigated downregulation of sigma-1R and effects of SA4503, a sigma-1 R agonist in transverse aortic constriction (TAC) model mice. Those mice exhibited heart failure with reduced sigma-1R levels in heart. The oral administration of SA4503 (0.1-1mg/kg) dose-dependently restored the reduced sigma-1R and ATP production in heart, thereby improving heart functions. Notably, the reduced sigma-1R was also observed in the central nervous system. Then, SA4503 treatments also improved impaired brain functions. We are now preparing sigma-1R(E102Q) mutant mice to investigate effects of mitochondrial function improvers including pyruvate, aminolevulinic acid and SA4503.
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Report
(3 results)
Research Products
(57 results)
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[Journal Article] Reduced CaM Kinase II and CaM Kinase IV Activities Underlie Cognitive Deficits in NCKX2 Heterozygous Mice.2018
Author(s)
Moriguchi S, Kita S, Yabuki Y, Inagaki R, Izumi H, Sasaki Y, Tagashira H, Horie K, Takeda J, Iwamoto T, Fukunaga K.
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Journal Title
Mol Neurobiol.
Volume: 55(5)
Pages: 3889-3900
DOI
Related Report
Peer Reviewed
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[Journal Article] Pharmacological properties of SAK3, a novel T-type voltage-gated Ca2+ channel enhancer.2017
Author(s)
Yabuki Y, Matsuo K, Izumi H, Haga H, Yoshida T, Wakamori M, Kakehi A, Sakimura K, Fukuda T, Fukunaga K.
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Journal Title
Neuropharmacology.
Volume: 117
Pages: 1-13
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Trans-fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway.2017
Author(s)
Hirata, Y., Takahashi, M., Kudoh, Y., Kano, K., Kawana, H., Makide, K., Shinoda, Y., Yabuki, Y., Fukunaga, K., Aoki, J., Noguchi, T., Matsuzawa, A.
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Journal Title
J. Biol. Chem.
Volume: 印刷中
Issue: 20
Pages: 8174-8185
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Blockade of the KATP channel Kir6.2 by memantine represents a novel mechanism relevant to Alzheimer's disease therapy.2016
Author(s)
Moriguchi S, Ishizuka T, Yabuki Y, Shioda N, Sasaki Y, Tagashira H, Yawo H, Yeh JZ, Sakagami H, Narahashi T, Fukunaga K.
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Journal Title
Mol Psychiatry.
Volume: 印刷中
Issue: 2
Pages: 211-221
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Endogenous Polysialic Acid Based Micelles for Calmodulin Antagonist Delivery against Vascular Dementia.2016
Author(s)
Wang XJ, Gao YP, Lu NN, Li WS, Xu JF, Ying XY, Wu G, Liao MH, Tan C, Shao LX, Lu YM, Zhang C, Fukunaga K, Han F, Du YZ.
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Journal Title
ACS Appl Mater Interfaces.
Volume: 8
Issue: 51
Pages: 35045-35058
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.2016
Author(s)
Huang JY, Tian Y, Wang HJ, Shen H, Wang H, Long S, Liao MH, Liu ZR, Wang ZM, Li D, Tao RR, Cui TT, Moriguchi S, Fukunaga K, Han F, Lu YM.
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Journal Title
CNS Neurosci Ther.
Volume: 22
Issue: 10
Pages: 845-853
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Stress-responsive heme oxygenase-1 isoenzyme participates in Toll-like receptor 4-induced inflammation during brain ischemia.2016
Author(s)
Wang R, Wang ST, Wang YD, Wu G, Du Y, Qian MQ, Liang XG, Elbatreek MH, Yang HY, Liu ZR, Fukunaga K, Liu JX, Lu YM.
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Journal Title
Neuroreport.
Volume: 27
Issue: 6
Pages: 445-454
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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