Neuroprotective γ-Pyrones from Fusarium Solani JS-0169: Cell-Based Identification of Active Compounds and an Informatics Approach to Predict the Mechanism of Action.

Hyun Gyu Choi,Ki Sung Kang,Ji Hoon Song,Musun Park,Chang-Eop Kim,Soonok Kim,Sang Hee Shim

doi:10.3390/biom10010091

Abstract

Glutamate toxicity has been implicated in neuronal cell death in both acute CNS injury and in chronic diseases. In our search for neuroprotective agents obtained from natural sources that inhibit glutamate toxicity, an endophytic fungus, Fusarium solani JS-0169 isolated from the leaves of Morus alba, was found to show potent inhibitory activity. Chemical investigation of the cultures of the fungus JS-0169 afforded isolation of six compounds, including one new γ-pyrone (1), a known γ-pyrone, fusarester D (2), and four known naphthoquinones: karuquinone B (3), javanicin (4), solaniol (5), and fusarubin (6). To identify the protective effects of the isolated compounds (1–6), we assessed their inhibitory effect against glutamate-induced cytotoxicity in HT22 cells. Among the isolates, compound 6 showed significant neuroprotective activity on glutamate-mediated HT22 cell death. In addition, the informatics approach using in silico systems pharmacology identified that compound 6 may exert its neuroprotective effect by controlling the amount of ubiquinone. The results suggest that the metabolites produced by the endophyte Fusarium solani JS-0169 might be related to the neuroprotective activity of its host plant, M. alba.

Highlights

Glutamate is a neurotransmitter that plays pivotal roles in various physiological as well as pathological brain functions
Fusarium solani JS-0169 was isolated from the leaves of a medicinal plant
Oxidative stress is a major event during neuronal cell death

Summary

Introduction

Glutamate is a neurotransmitter that plays pivotal roles in various physiological as well as pathological brain functions. Excessive amounts of glutamate induce oxidative stress-mediated neuronal cell death through both acute brain injuries and neurodegenerative diseases [1]. Reactive oxygen species (ROS) are the major causes of neuronal cell death in chronic neurodegenerative diseases [2]. Earlier studies have shown that excessive release of glutamate in the extracellular environment blocks cysteine uptake and depletes intracellular glutathione (GSH) levels, leading to an accumulation of ROS intracellularly [3]. The use of natural antioxidative phytochemicals for scavenging the free radicals and maintaining homeostasis contributes to alleviation of neuronal cell death [4]. Natural compounds are multiple-target molecules found mainly in microorganisms

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