Elucidation of the mechanism of action of novel antiepileptic drugs using functionalized magnetic nanoparticles and exploration of their neuroprotective effects

2019 Fiscal Year Final Research Report

• Project/Area Number: 16K10000
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tokyo Medical University
• Principal Investigator: Yamanaka Gaku 東京医科大学, 医学部, 准教授 (70349512)
• Co-Investigator(Kenkyū-buntansha): 石 龍徳 東京医科大学, 医学部, 主任教授 (20175417) ; 河島 尚志 東京医科大学, 医学部, 主任教授 (70224772) ; 半田 宏 東京医科大学, 医学部, 特任教授 (80107432) ; 善本 隆之 東京医科大学, 医学部, 教授 (80202406) ; 松本 哲哉 東京医科大学, 医学部, 兼任教授 (10256688) ; 出雲 信夫 横浜薬科大学, 薬学部, 教授 (70368976)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Keywords: サイトカイン / 急性脳症 / てんかん / 新規抗てんかん薬 / アポトーシス / 炎症

Outline of Final Research Achievements

The pathogenesis of acute encephalopathy and epilepsy is still unclear and new treatments are desired. We identified a candidate protein for levetiracetam (LEV) using functional nanomagnetic particles. In a mouse model of encephalopathy, we observed a tendency to decrease IL-1β and IL-6 mRNA in the cerebral cortex after administration of LEV. However, there was no evident difference between the effects of diazepam and those of LEV, and the mechanism of action of LEV could not be elucidated. Cerebrospinal fluid levels of Granzyme A and pro-inflammatory cytokines were significantly higher in the Infection-associated acute encephalopathy than in the control group. In refractory epilepsy patients, intracellular cytokines (monocytes;IL-1β,TNF-α、CD8T cells;IL-17 and NK cells; IFN-γ) were significantly higher compare to the control group. These results suggest the intervention of immunological mechanisms in the pathogenesis of acute encephalopathy and epilepsy.

Free Research Field

小児神経学

Academic Significance and Societal Importance of the Research Achievements

脳症モデルマウスの検討にて、LEVによる炎症性サイトカインの低下が大脳皮質のmRNAレベルで確認され、抗てんかん薬による免疫学的機序の関与が示唆された。急性脳症の病態にGranzyme Aを介したアポトーシスの関与、てんかんの病態に血清や髄液だけではなく、細胞内の炎症性サイトカインの上昇が確認された。急性脳症やてんかんの病態に炎症やアポトーシスに伴う免疫学的機序の関与が明らかになれば、新たな治療法に繋がる可能性がある。