2(3H)-Dihydrofranolactone metabolites from Pleosporales sp. NUH322 as anti-amyotrophic lateral sclerosis drugs.

Autor: Kusama-Eguchi, Kuniko, Tokui, Yuki, Minoura, Ai, Yanai, Yuta, Hirose, Dai, Furukawa, Megumi, Kosuge, Yasuhiro, Miura, Motofumi, Ohkoshi, Emika, Makino, Mitsuko, Minagawa, Kimino, Matsuzaki, Keiichi, Ogawa, Yoshio, Watanabe, Kazuko, Ohsaki, Ayumi
Zdroj: Journal of Natural Medicines; Jan2024, Vol. 78 Issue 1, p146-159, 14p
Abstrakt: Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3–7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001–0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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