Drug development improving mitochondrial pathology in Amyotrophic lateral sclerosis

• Project/Area Number: 16K14574
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Neurochemistry/Neuropharmacology
• Research Institution: Tohoku University
• Principal Investigator: Fukunaga Kohji 東北大学, 薬学研究科, 教授 (90136721)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥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)
• 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

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.

Research Products

• [Journal Article] Acute Treatment with T-Type Calcium Channel Enhancer SAK3 Reduces Cognitive Impairments Caused by Methimazole-Induced Hypothyroidism Via Activation of Cholinergic Signaling. (2018)
  • Author(s): Husain N, Yabuki Y, Shinoda Y, Fukunaga K.
  • Journal Title: Pharmacology. Volume: 101 Issue: 5-6 Pages: 309-321
  • DOI: 10.1159/000488083
  • Peer Reviewed
• [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.
  • Journal Title: Mol Neurobiol. Volume: 55(5) Pages: 3889-3900
  • DOI: 10.1007/s12035-017-0596-1
  • Peer Reviewed
• [Journal Article] Pathophysiological role of sigma-1 receptor in Amyotrophic lateral sclerosis (2017)
  • Author(s): 福永 浩司、篠田 康晴
  • Journal Title: 生化学 Volume: 89 Issue: 1 Pages: 106-110
  • DOI: 10.14952/SEIKAGAKU.2017.890106
  • NAID: 40021119824
  • ISSN: 0037-1017
  • Year and Date: 2017-02-25
• [Journal Article] The T-type calcium channel enhancer SAK3 inhibits neuronal death following transient brain ischemia via nicotinic acetylcholine receptor stimulation. (2017)
  • Author(s): Yabuki Y, Jing X, Fukunaga K.
  • Journal Title: Neurochem Int. Volume: 108 Pages: 272-281
  • DOI: 10.1016/j.neuint.2017.04.015
  • Peer Reviewed
• [Journal Article] Novel spiroimidazopyridine derivative SAK3 improves methimazole-induced cognitive deficits in mice. (2017)
  • Author(s): Noreen H, Yabuki Y, Fukunaga K.
  • Journal Title: Neurochem Int. Volume: - Pages: 91-99
  • DOI: 10.1016/j.neuint.2017.03.001
  • Peer Reviewed
• [Journal Article] Stimulation of the Sigma-1 Receptor and the Effects on Neurogenesis and Depressive Behaviors in Mice. (2017)
  • Author(s): Fukunaga K, Moriguchi S.
  • Journal Title: Adv Exp Med Biol. Volume: 964 Pages: 201-211
  • DOI: 10.1007/978-3-319-50174-1_14
  • ISBN: 9783319501727, 9783319501741
  • Peer Reviewed
• [Journal Article] Combined l-citrulline and glutathione administration prevents neuronal cell death following transient brain ischemia. (2017)
  • Author(s): Matsuo K, Yabuki Y, Fukunaga K.
  • Journal Title: Brain Res. Volume: 1663 Pages: 123-131
  • DOI: 10.1016/j.brainres.2017.03.014
  • Peer Reviewed
• [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.
  • Journal Title: Neuropharmacology. Volume: 117 Pages: 1-13
  • DOI: 10.1016/j.neuropharm.2017.01.011
  • Peer Reviewed / Open Access
• [Journal Article] Combined Memantine and Donepezil Treatment Improves Behavioral and Psychological Symptoms of Dementia-Like Behaviors in Olfactory Bulbectomized Mice. (2017)
  • Author(s): Yabuki Y, Matsuo K, Hirano K, Shinoda Y, Moriguchi S, Fukunaga K.
  • Journal Title: Pharmacology Volume: 99 Issue: 3-4 Pages: 160-171
  • DOI: 10.1159/000452839
  • Peer Reviewed
• [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.
  • Journal Title: J. Biol. Chem. Volume: 印刷中 Issue: 20 Pages: 8174-8185
  • DOI: 10.1074/jbc.m116.771519
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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.
  • Journal Title: Mol Psychiatry. Volume: 印刷中 Issue: 2 Pages: 211-221
  • DOI: 10.1038/mp.2016.187
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Endocytosis following dopamine D2 receptor activation is critical for neuronal activity and dendritic spine formation via Rabex-5/PDGFRβ signaling in striatopallidal medium spiny neurons. (2016)
  • Author(s): Shioda N*, Yabuki Y, Wang Y, Uchigashima M, Hikida T, Sasaoka T, Mori H, Watanabe M, Sasahara M, Fukunaga K
  • Journal Title: Molecular Psychiatry Volume: 印刷中 Issue: 8 Pages: 1205-1222
  • DOI: 10.1038/mp.2016.200
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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.
  • Journal Title: ACS Appl Mater Interfaces. Volume: 8 Issue: 51 Pages: 35045-35058
  • DOI: 10.1021/acsami.6b13052
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Corticosteroids Mediate Heart Failure-Induced Depression through Reduced σ1-Receptor Expression. (2016)
  • Author(s): Shinoda Y, Tagashira H, Bhuiyan MS, Hasegawa H, Kanai H, Zhang C, Han F, Fukunaga K.
  • Journal Title: PLoS One. Volume: 11 Issue: 10 Pages: 1-19
  • DOI: 10.1371/journal.pone.0163992
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Haloperidol aggravates transverse aortic constriction-induced heart failure via mitochondrial dysfunction. (2016)
  • Author(s): Shinoda Y, Tagashira H, Bhuiyan MS, Hasegawa H, Kanai H, Fukunaga K.
  • Journal Title: J Pharmacol Sci. Volume: 131 Issue: 3 Pages: 172-183
  • DOI: 10.1016/j.jphs.2016.05.012
  • Peer Reviewed / Int'l Joint Research
• [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.
  • Journal Title: CNS Neurosci Ther. Volume: 22 Issue: 10 Pages: 845-853
  • DOI: 10.1111/cns.12582
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stimulation of sigma-1 receptor ameliorates depressive-like behaviors via mitochondrial ATP production in CaMKIV null mice (2016)
  • Author(s): Shigeki Moriguchi, Hiroyuki Sakagami, Yasushi Yabuki, Yuzuru Sasaki, Hisanao Izumi, Chen Zhang, Feng Han and Kohji Fukunaga
  • Journal Title: Folia Pharmacologica Japonica Volume: 147 Issue: 4 Pages: 206-210
  • DOI: 10.1254/fpj.147.206
  • NAID: 130005143840
  • ISSN: 0015-5691, 1347-8397
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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.
  • Journal Title: Neuroreport. Volume: 27 Issue: 6 Pages: 445-454
  • DOI: 10.1097/wnr.0000000000000561
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Arachidonic acid treatment aggravates alpha-Synuclein aggregation in vitro and in situ (2018)
  • Author(s): ○Kohji Fukunaga, Yasushi Yabuki, Kazuya Matsuo, Yasuharu Shinoda
  • Organizer: AD/PD 2018
• [Presentation] Arachidonic acid treatment aggravates alpha-Synuclein aggregation in vitro and in situ (2018)
  • Author(s): ○Yasuharu Shinoda, An Cheng, Tetsunori Yamamoto, Yasushi Kawata, Kohji Fukunaga
  • Organizer: AD/PD 2018
• [Presentation] Arachidonic acid promotes alpha-synuclein oligomerization through fatty acid-binding proteins. (2017)
  • Author(s): Kohji Fukunaga, Yasushi Yabuki, Yasuharu Shinoda, Hisanao Izumi
  • Organizer: The 13th International Conference on Alzheimer's & Parkinson's Diseases
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-03-29
  • Int'l Joint Research
• [Presentation] Preclinical studies of T-type calcium channel enhancer in Alzheimer's disease therapy. (2017)
  • Author(s): Kohji Fukunaga, Hisanao Izumi, Yasuharu Shinoda, Yasushi Yabuki
  • Organizer: The 13th International Conference on Alzheimer's & Parkinson's Diseases
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-03-29
  • Int'l Joint Research
• [Presentation] T 型カルシウムチャネル活性化薬SAK3は嗅球摘出マウスの海馬神経新生を促進する (2017)
  • Author(s): 矢吹悌、許晶、福永浩司
  • Organizer: 第90回日本薬理学会年会
  • Place of Presentation: 長崎
  • Year and Date: 2017-03-15
• [Presentation] FABP3 deficiency impairs fear extinction memory (2017)
  • Author(s): ○Yasushi Yabuki, Ibuki Takahata, Kazuya Mastuo, Yuji Owada, Kohji Fukunaga
  • Organizer: Neuroscience 2017
• [Presentation] Mitochondrial dysfunction and oxidative stress in rat brain prenatally exposed to valproic acid (2017)
  • Author(s): ○Kazuya Matsuo, Yasushi Yabuki, and Kohji Fukunaga
  • Organizer: Neuroscience 2017
• [Presentation] Discovery of a novel intracellular dopamine D2 receptor function (2017)
  • Author(s): ○Kohji Fukunaga, Norifumi Shioda
  • Organizer: 第60回日本神経化学会大会
• [Presentation] Preclinical Studies of SAK3, a T-type Calcium Channel Stimulator in APP23 mice and rats. (2016)
  • Author(s): Kohji Fukunaga, Hisanao Izumi, Yasuharu Shinoda, Yasushi Yabuki
  • Organizer: CTAD2016 - Clinical Trials on Alzheimer's Disease
  • Place of Presentation: San Diego, USA
  • Year and Date: 2016-12-08
  • Int'l Joint Research
• [Presentation] 脂肪酸結合タンパク質は黒質ドパミン神経細胞におけαシヌクレイン凝集体形成に関与する (2016)
  • Author(s): 福永浩司、矢吹悌、塩田倫史
  • Organizer: 第59回 日本脳循環代謝学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2016-11-11
• [Presentation] T 型カルシウムチャネル活性化薬 SAK3 の神経保護作用 (2016)
  • Author(s): 矢吹悌、許晶、福永浩司
  • Organizer: 第59回 日本脳循環代謝学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2016-11-11
• [Presentation] 新規認知症治療候補薬（SAK3:T型電位依存性Ca2+ チャネル活性化薬）による脳梗塞縮小効果 (2016)
  • Author(s): 笠原直子、脇坂義信、吾郷哲朗、立花正輝、吉川容司、古森元浩、芝原友也、黒田淳哉、松尾龍、福永浩司、北園孝成
  • Organizer: 第59回 日本脳循環代謝学術集会
  • Place of Presentation: 徳島
  • Year and Date: 2016-11-11
• [Presentation] Lacking of dopamine D2L receptor causes vulnerability against chronic stress. (2016)
  • Author(s): Kohji Fukunaga
  • Organizer: 12th International Conference on Protein Phosphatase (ICPP12)
  • Place of Presentation: 大阪
  • Year and Date: 2016-10-27
• [Presentation] A Novel Alzheimer’s Disease Therapy Candidates Target T-type Calcium Channels and KATP Channels. (2016)
  • Author(s): Kohji Fukunaga
  • Organizer: Zhejiang Xiaochan Hospital Memorial Lecture
  • Place of Presentation: Zhejiang Xiaochan Hospital, Hangzhou
  • Year and Date: 2016-10-13
  • Int'l Joint Research / Invited
• [Presentation] シグマ１受容体発現量の低下と心不全誘導うつ様症状の関連性 (2016)
  • Author(s): 篠田康晴、田頭秀章、福永浩司
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 仙台
  • Year and Date: 2016-09-25
• [Presentation] Crucial Roles of sigma-1 receptor in amyotrophic lateral sclerosis (ALS) therapy. (2016)
  • Author(s): Kohji Fukunaga and Yasuharu Shinoda
  • Organizer: Protein misfolding in disease-toxic aggregation-prone proteins in aging and age-related diseases: From structure to pathology and spreading
  • Place of Presentation: Roscoff, France
  • Year and Date: 2016-09-12
  • Int'l Joint Research
• [Presentation] PTSD-like behavior in FABP3 null mice and its improvement by melatonin agonist (2016)
  • Author(s): 福永浩司、矢吹悌、大和田裕二
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会 合同年会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
• [Presentation] Reduced CaM kinase II and CaM kinase IV activities mediate cognitive deficits in NCKX2 heterozygous mice (2016)
  • Author(s): 森口茂樹、喜多紗斗美、矢吹悌、堀江恭二、竹田潤二、岩本隆宏、福永浩司
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会 合同年会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
• [Presentation] 海馬依存性記憶形成におけるT型カルシウムチャネルの関与 (2016)
  • Author(s): 矢吹 悌、松尾 和哉、若森 実、福永 浩司
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会 合同年会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
• [Presentation] ハロペリドールによるシグマ１受容体の阻害は心不全病態を悪化させる (2016)
  • Author(s): 篠田康晴、田頭秀章、福永浩司
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会 合同年会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
• [Presentation] 前帯状皮質GABAシステム制御機構における脂肪酸結合タンパク質の役割 (2016)
  • Author(s): 山本由似、福永浩司、大和田裕二
  • Organizer: 第38回日本生物学的精神医学会・第59回日本神経化学会大会 合同年会
  • Place of Presentation: 福岡
  • Year and Date: 2016-09-08
• [Presentation] Curcuminoid Prevents Nicotine Dependence Symptom and Nicotine Relapse in Mice. (2016)
  • Author(s): Gofarana Wilar, Kohji Fukunaga, Kusnandar Anggadiredja
  • Organizer: The International Seminar on Pharmacology and Clinical Pharmacy 2016
  • Place of Presentation: インドネシア
  • Year and Date: 2016-09-01
• [Presentation] Novel cognitive enhancer SAK3 improves cognitive impairments by methimazole-induced hypothyroidism (2016)
  • Author(s): Noreen Husain, Yasushi Yabuki, Kohji Fukunaga
  • Organizer: 14th Meeting of The Asian-Pacific Society for Neurochemistry
  • Place of Presentation: クアラルンプール
  • Year and Date: 2016-08-27
• [Presentation] 一過性脳虚血発作が誘導する eNOS S-glutathionylation と L-シトルリン・グルタチオン併用投与による脳保護効果 (2016)
  • Author(s): 矢吹悌、福永浩司
  • Organizer: 生体機能と創薬シンポジウム2016
  • Place of Presentation: 仙台
  • Year and Date: 2016-08-25
• [Presentation] APP23マウスに対するアルツハイマー病治療候補薬SAK3の薬効と体内動態 (2016)
  • Author(s): 泉久尚、矢吹悌、篠田康晴、福永浩司
  • Organizer: 生体機能と創薬シンポジウム2016
  • Place of Presentation: 仙台
  • Year and Date: 2016-08-25
• [Presentation] MPTP 誘発パーキンソン病様症状に対するピルビン酸エチルの改善作用 (2016)
  • Author(s): 芳賀飛高、矢吹悌、福永浩司
  • Organizer: 生体機能と創薬シンポジウム2016
  • Place of Presentation: 仙台
  • Year and Date: 2016-08-25
• [Presentation] Atrx 遺伝子改変マウスにおける知的障害機構の解析 (2016)
  • Author(s): 山口航矢、塩田倫史、福永浩司
  • Organizer: 生体機能と創薬シンポジウム2016
  • Place of Presentation: 仙台
  • Year and Date: 2016-08-25
• [Presentation] 胎生期バルプロ酸曝露による自閉症様行動とオキシトシンによる改善効果 (2016)
  • Author(s): 松尾和哉、矢吹悌、福永浩司
  • Organizer: 生体機能と創薬シンポジウム2016
  • Place of Presentation: 仙台
  • Year and Date: 2016-08-25
• [Presentation] ATR-X 遺伝子改変マウスを用いた知的障害機構の解析 (2016)
  • Author(s): 山口航矢、塩田倫史、福永浩司
  • Organizer: 第27回霧島神経薬理フォーラム
  • Place of Presentation: 福岡
  • Year and Date: 2016-08-19
• [Presentation] MPTP 誘発パーキンソン病様症状に対するミトコドリア保護薬の効果 (2016)
  • Author(s): 芳賀飛高、矢吹悌、福永浩司
  • Organizer: 第27回霧島神経薬理フォーラム
  • Place of Presentation: 福岡
  • Year and Date: 2016-08-19
• [Presentation] 経口グルタチオン投与の脳血管性認知症の予防効果 (2016)
  • Author(s): 福永浩司、矢吹悌
  • Organizer: 第18回応用薬理シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2016-08-05
• [Presentation] 難治性うつ病の新たな治療展開 (2016)
  • Author(s): 森口茂樹、福永浩司
  • Organizer: 第18回応用薬理シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2016-08-05
• [Presentation] オキシトシン投与は胎生期バルプロ酸曝露による自閉症様行動を改善する (2016)
  • Author(s): 松尾和哉、矢吹悌、福永浩司
  • Organizer: 第18回応用薬理シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2016-08-05
• [Presentation] T 型 Ca2+ チャネル活性化作用を有する spiroimidazopyridine 化合物の生理活性評価 (2016)
  • Author(s): 矢吹悌、福永浩司
  • Organizer: 第68回日本細胞生物学会・第11回日本ケミカルバイオロジー学会 合同大会
  • Place of Presentation: 京都
  • Year and Date: 2016-06-15
• [Presentation] 圧負荷心肥大モデルマウスのうつ様行動へのシグマ1受容体の関与 (2016)
  • Author(s): 篠田康晴、田頭秀章、福永浩司
  • Organizer: 第26回日本循環薬理学会
  • Place of Presentation: 松本
• [Presentation] バナジウム有機錯体 VO(OPT) 投与による脳虚血耐性誘導 (2016)
  • Author(s): 高畑伊吹、矢吹悌、福永浩司
  • Organizer: 第67回日本薬理学会北部会
  • Place of Presentation: 札幌
• [Presentation] アルツハイマー病治療候補薬SAK3の心毒性に関する研究 (2016)
  • Author(s): 田原一樹、篠田康晴、矢吹悌、福永浩司
  • Organizer: 第67回日本薬理学会北部会
  • Place of Presentation: 札幌
• [Presentation] ドパミンD2L 受容体欠損マウスにおける精神ストレス脆弱性のメカニズム (2016)
  • Author(s): 杉本航、塩田倫史、福永浩司
  • Organizer: 第67回日本薬理学会北部会
  • Place of Presentation: 札幌
• [Presentation] 胎生期バルプロ酸曝露による自閉症様行動に対するオキシトシンの改善作用 (2016)
  • Author(s): 松尾 和哉、矢吹 悌、福永 浩司
  • Organizer: 次世代を担う創薬・医療薬理シンポジウム2016
  • Place of Presentation: 仙台