Development of novel therapeutics for Parkinson disease by FABP3 ligands

• Project/Area Number: 15H06036
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pharmacology in pharmacy
• Research Institution: Tohoku University
• Principal Investigator: YABUKI Yasushi 東北大学, 薬学研究科, 助教 (70756121)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2016: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: パーキンソン病 / α-シヌクレイン / FABP3 / 薬理学 / 薬学 / 脳神経疾患 / 神経科学

Outline of Final Research Achievements

α-synuclein is one of major components in lewy bodies and its aggregates promotes neurodegeneration and cell death in dopaminergic neurons, thereby triggering Parkinson disease. Fatty acid binding protein 3 (FABP3) aggravates MPTP-induced α-synuclein oligomerizations in mouse dopaminergic neurons. In the present study, we investigated whether FABP3 ligands prevent α-synuclein oligomerizations and motor impairments in Parkinson models. In vitro assay, FABP3 ligands significantly inhibited MPP+-induced α-synuclein oligomerizations in both α-synuclein and FABP3 over-expressed PC12 cells. In addition, oral administration of FABP3 ligands significantly prevented α-synuclein oligomerizations and cell death in dopaminergic neurons in the substantia nigra, thereby improving motor impairments seen in animal model of Parkinson disease. Taken together, those results suggest that FABP3 ligands may be attractive candidate of novel therapeutics for Parkinson disease.

Research Products

• [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] 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] 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] 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] 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] 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] ehydroepiandrosterone administration improves memory deficits following transient brain ischemia through sigma-1 receptor stimulation. (2015)
  • Author(s): Yabuki Y, Shinoda Y, Izumi H, Ikuno T, Shioda N, Fukunaga K.
  • Journal Title: Brain Reｓｅａｒｃｈ Volume: 1622 Pages: 102-113
  • DOI: 10.1016/j.brainres.2015.05.006
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Stimulation of Sigma-1 Receptor Ameliorates Depressive-like Behaviors in CaMKIV Null Mice. (2015)
  • Author(s): Moriguchi, S.;Sakagami, H.;Yabuki, Y.;Sasaki, Y.;Izumi, H.;Zhang, C.;Han, F.;Fukunaga, K.
  • Journal Title: Mol Neurobiol Volume: 52 Issue: 3 Pages: 1210-1222
  • DOI: 10.1007/s12035-014-8923-2
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [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] 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] 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] 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] 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] S-glutathionylationn of endothelial nitric oxide synthase following transient brain ischemia. (2016)
  • Author(s): Yasushi Yabuki, Kohji Fukunaga
  • Organizer: The 9th International Conference on the Biology, Chemistry, and Therapeutic Applications of Nitric Oxide - The 16th Annual Scientific Meeting of the Nitric Oxide Society of Japan
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-20
  • Int'l Joint Research
• [Presentation] Cognitive improvement by SAK3 through T-type voltage gated Ca2+ channel stimulation (2016)
  • Author(s): Yasushi Yabuki and Kohji Fukunaga
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-09
• [Presentation] T-type Ca2+ channel activation by spiroimidazopyridine compound. (2015)
  • Author(s): Yasushi Yabuki, Minoru Wakamori, and Kohji Fukunaga
  • Organizer: Pharmaceutical Science Symposium 2015 in Sendai
  • Place of Presentation: 仙台
  • Year and Date: 2015-11-16
  • Int'l Joint Research
• [Presentation] Alzheimer disease drug candidate SAK3 stimulates cav3.1 and cav3.3 t-type calcium channels. (2015)
  • Author(s): Yasushi Yabuki, Minoru Wakamori, and Kohji Fukunaga
  • Organizer: Neuroscience 2015
  • Place of Presentation: Chicago, USA
  • Year and Date: 2015-10-17
  • Int'l Joint Research
• [Presentation] Anxiety and PTSD-like behaviors in FABP3 null mice. (2015)
  • Author(s): Yasushi Yabuki, Ibuki Takahata, Ryo Inagaki, Yuji Owada, Kohji Fukunaga
  • Organizer: 第45回日本神経精神薬理学会・第37回日本生物学的精神医学会合同年会
  • Place of Presentation: 東京
  • Year and Date: 2015-09-24
• [Presentation] Effect of a novel cognitive enhancer ST101 on decreased CaMKII activity in schizophrenia model rats. (2015)
  • Author(s): Yasushi Yabuki and Kohji Fukunaga
  • Organizer: 第58回日本神経化学会大会
  • Place of Presentation: 埼玉
  • Year and Date: 2015-09-11
• [Patent(Industrial Property Rights)] シヌクレイノパチー治療薬 (2017)
  • Inventor(s): 福永 浩司
  • Industrial Property Rights Holder: 福永 浩司
  • Industrial Property Rights Type: 特許
  • Filing Date: 2017-03-31