As soy-derived glyceollins are known to induce antioxidant enzymes in various types\nof cells and tissues, we hypothesized that the compounds could protect neurons from damage\ndue to reactive oxygen species (ROS). In order to examine the neuroprotective effect of glyceollins,\nprimary cortical neurons collected from mice and mouse hippocampal HT22 cells were challenged\nwith glutamate. Glyceollins attenuated glutamate-induced cytotoxicity in primary cortical neuron\nisolated from mice carrying wild-type nuclear factor (erythroid-derived 2)-like 2 (Nrf2), but the\ncompounds were ineffective in those isolated from Nrf2 knockout mice, suggesting the involvement\nof the Nrf2 signaling pathway in glyceollin-mediated neuroprotection. Furthermore, the inhibition\nof heme oxygenase-1 (HO-1), a major downstream enzyme of Nrf2, abolished the suppressive\neffect of glyceollins against glutamate-induced ROS production and cytotoxicity, confirming that\nactivation of HO-1 by glyceollins is responsible for the neuroprotection. To examine whether\nglyceollins also improve cognitive ability, mice pretreated with glyceollins were challenged with\nscopolamine and subjected to behavioral tests. Glyceollins attenuated scopolamine-induced cognitive\nimpairment of mice, but failed to enhance memory in Nrf2 knockout mice, suggesting that the\nmemory-enhancing effect is also mediated by the Nrf2 signaling pathway. Overall, glyceollins\nshowed neuroprotection against glutamate-induced damage, and attenuated scopolamine-induced\nmemory deficits in an Nrf2-dependent manner.
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