Development of therapeutic agents targeting HMGB1 in brain.

2019 Fiscal Year Final Research Report

• Project/Area Number: 19K21225
• Project/Area Number (Other): 18H06106 (2018)
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund (2019); Single-year Grants (2018)
• Review Section: 0801:Pharmaceutical sciences and related fields
• Research Institution: Hiroshima University
• Principal Investigator: Nakamura Yoki 広島大学, 医系科学研究科(薬), 助教 (60711786)
• Project Period (FY): 2018-08-24 – 2020-03-31
• Keywords: HMGB1 / 慢性疼痛 / DAMPs / 脳内疼痛制御機構 / 脳内炎症 / パーキンソン病

Outline of Final Research Achievements

Previous studies reported that high mobility group box-1 (HMGB1) in spinal dorsal horn and around injured-sciatic nerve plays an important role in both induction and maintenance phases of chronic pain. However, it is unclear whether HMGB1 in brain is involved in pain regulation. Here, we found that intraventricular injection with recombinant HMGB1 induced mechanical hypersensitivity. Moreover, inhibition of HMGB1 function in brain can ameliorate the maintenance, not induction, phase of mechanical hypersensitivity with 6-hydroxy dopamine model of Parkinson's disease in mouse. These data suggested that blocking HMGB1 function could prove to be a potent therapeutic strategy for the treatment of refractory pain associated with neurodegenerative disorders.

Free Research Field

神経薬理学、疼痛学、創薬研究

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、脊髄などと同様に脳内の HMGB1 も疼痛の調節機構に関与する可能性を明らかにした。さらに、これまでに有効な治療法が確立されていなかったパーキンソン病などの神経変性疾患に付随する疼痛症状の根底にあるメカニズムの一旦を HMGB1 が担っている可能性が示唆された。脳内HMGB1 を新規鎮痛薬の創薬ターゲットととするための基礎的知見を提供し、治療法の確立されていない難治性疼痛に対する創薬開発への貢献が期待できる。