Elucidation of optic nerve protection via inhibition of p38-p62 signal

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K18894
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: St. Marianna University School of Medicine
• Principal Investigator: Sase Kana 聖マリアンナ医科大学, 医学部, 助教 (30821904)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: オートファジー / ｐ62 / p-p38

Outline of Final Research Achievements

Akebia Saponin D (ASD), an autophagy inducer, exert axonal protection in optic nerve. A previous report showed that ASD suppress MAPK signals. The result of western blot showed that the expression of p-p38 and p62 was significantly elevated by TNF injection and this elevation was significantly suppressed by ASD. The peak of p-p38 elevation was 1 week after TNF injection, whereas significant elevations of p62 were observed at both 1 and 2 weeks, implicating that p-p38 exists upstream of p62. Treatment with ASD can inhibit this pathway, thereby exerting axonal protection.
SB20350, p38 inhibitor showed significant axonal protection in TNF-induced optic nerve degeneration model. The result of western blot showed the level of p62 was significantly increased by TNF injection. This TNF-increased p62 expression was significantly decreased by SB203580.
These results suggest that inhibition of p38 exerts axonal protection with upregulated autophagy in TNF-induced optic nerve damage.

Free Research Field

緑内障視神経保護

Academic Significance and Societal Importance of the Research Achievements

緑内障患者で薬剤、手術により十分な眼圧下降が得られても視野障害の進行を阻止できない患者には眼圧非依存性の根本的治療が必要である。緑内障の病態は視神経軸索障害であることは視神経乳頭のリムの菲薄化と一致する神経線維層欠損から明らかであり、視神経軸索保護効果を有する様々な治療が期待される。p38は多くの炎症系疾患に関与しているとされていて、関節リウマチの治療薬としてp38阻害剤が臨床試験まで進んでいる。pヒトですでに安全性が確立されたものの中で視神経軸索保護効果を示すものを明らかにできれば、投与経路等も検討した上で、将来的に緑内障治療の新たな選択肢を見出せる可能性がある。