Elucidation of the cerebral ischemic tolerance by inducing UCP4 expression, and challenging of the novel therapeutic approach for cerebral infarct

• Project/Area Number: 18K16555
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Shizuoka University (2022); Hamamatsu University School of Medicine (2018-2021)
• Principal Investigator: Fukushi Yasuko 静岡大学, 電子工学研究所, 学術研究員 (50722683)
• Project Period (FY): 2018-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
• Keywords: ミトコンドリア脱共役蛋白質 / 脳虚血 / 神経保護 / 虚血性神経細胞障害 / 低酸素 / 脳電気刺激

Outline of Final Research Achievements

The mitochondrial uncoupling protein 4 (UCP4) is thought to play an important role in acquiring ischemic tolerance in cerebral infarction by electrical stimulation of the cerebellar fastigial nucleus (FN). In this study, we elucidated the mechanism of UCP4 expression induction. It was suggested that UCP4 expression was significantly increased in cerebral cortical neurons by FN stimulation, although the expression of UCP4 varied depending on the brain region. UCP4 expression was enhanced by carbachol administration and suppressed by atropine, indicating that FN electrical stimulation activates the cholinergic pathway and acts on the cerebral cortex to induce UCP4 expression. The expression of UCP4 might suppress the generation of reactive oxygen species and prevents cell death, thus contributing to neuroprotection.

Academic Significance and Societal Importance of the Research Achievements

UCP4の役割や機能については一定の見解が得られていないものの、脳梗塞の細胞死を抑制できる可能性だけではなく、アルツハイマー病の治療にも関係する可能性が考えられ（アルツハイマー病ではUCP4の発現が低下していることが報告されている）、新たな治療戦略としても期待される。

Research Products

• [Journal Article] The Cholinergic Pathway and MitoKATP Induce UCP4 Expression Involved in Neuroprotection of FN Stimulation in Rats. (2022)
  • Author(s): Fukushi, Y., Golanov, E.V., Koizumi, S., Thura, M., Ihara, H., and Yamamoto, S
  • Journal Title: Stroke: Vascular and Interventional Neurology Volume: ２ Issue: 6 Pages: 1-12
  • DOI: 10.1161/svin.122.000362
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Astrocytes Protect Neurons in the Hippocampal CA3 Against Ischemia by Suppressing the Intracellular Ca2+ Overload (2018)
  • Author(s): Chuanqi Sun, Yasuko Fukushi, Yong Wang, Seiji Yamamoto
  • Journal Title: Frontiers in Cellular Neuroscience Volume: 12 Pages: 1-10
  • DOI: 10.3389/fncel.2018.00280
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Contribution of astrocytes related to neuroprotection against delayed neuronal cell death in hippocampus (2019)
  • Author(s): Yasuko Fukushi, Chuanqi Sun, Seiji Yamamoto
  • Organizer: Brain and Brain PET 2019
  • Int'l Joint Research
• [Presentation] Expression of Mitochondrial Uncoupling Protein 4 (UCP4) in Association with ATP-dependent K+ Channel Opening in Neuron (2019)
  • Author(s): Yasuko Fukushi, Chuanqi Sun, Seiji Yamamoto
  • Organizer: Neuroscience 2019
  • Int'l Joint Research
• [Presentation] Carbachol induces expression of the mitochondrial uncoupling protein 4 (UCP4) in neurons (2018)
  • Author(s): 福司康子、孫伝奇、山本清二
  • Organizer: 第41回日本神経科学大会