| Summary: | 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, <i>Fusarium solani</i> JS-0169 isolated from the leaves of <i>Morus alba</i>, 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 (<b>1</b>), a known γ-pyrone, fusarester D (<b>2</b>), and four known naphthoquinones: karuquinone B (<b>3</b>), javanicin (<b>4</b>), solaniol (<b>5</b>), and fusarubin (<b>6</b>). To identify the protective effects of the isolated compounds (<b>1</b>−<b>6</b>), we assessed their inhibitory effect against glutamate-induced cytotoxicity in HT22 cells. Among the isolates, compound <b>6</b> showed significant neuroprotective activity on glutamate-mediated HT22 cell death. In addition, the informatics approach using in silico systems pharmacology identified that compound <b>6</b> may exert its neuroprotective effect by controlling the amount of ubiquinone. The results suggest that the metabolites produced by the endophyte <i>Fusarium solani</i> JS-0169 might be related to the neuroprotective activity of its host plant, <i>M. alba</i>.
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