Neolignans from <i>Aristolochia fordiana</i> Prevent Oxidative Stress-Induced Neuronal Death through Maintaining the Nrf2/HO‑1 Pathway in HT22 Cells

Bioassay-guided fractionation of the ethanolic extract of the stems of <i>Aristolochia fordiana</i> led to the isolation of six new dihydrobenzofuran neolignans (<b>1</b>–<b>3</b> and <b>7</b>–<b>9</b>), three new 2-aryldihydrobenzofurans (<b>4</b>–<b>6</b>), a new 8-<i>O</i>-4′ neolignan (<b>10</b>), and 14 known analogues (<b>11</b>–<b>24</b>). The structures of compounds <b>1</b>–<b>10</b> were established by spectroscopic methods, and their absolute configurations were determined by analyses of the specific rotation and electronic circular dichroism data. The neuroprotective effects of compounds <b>1</b>–<b>24</b> against glutamate-induced cell death were tested in hippocampal neuronal cell line HT22. Compounds <b>17</b> and <b>20</b>–<b>24</b> exhibited moderate neuroprotective activity by increasing the endogenous antioxidant defense system. In addition, the neolignans activated the Nrf2 (nuclear factor E2-related factor 2) pathway, resulting in the increase of the expression of endogenous antioxidant protein HO-1 (heme oxygenase-1). The active compounds also preserved the levels of antiapoptotic protein Bcl-2 (B cell lymphoma/leukemia-2), which was decreased by glutamate. Collectively, these results suggested that the active neolignans protect neurons against glutamate-induced cell death through maintaining the Nrf2/HO-1 signaling pathway as well as preserving the Bcl-2 protein and might be promising novel beneficial agents for oxidative stress-associated diseases