The Bioactive Gamma-Oryzanol from Oryza sativa L. Promotes Neuronal Differentiation in Different In Vitro and In Vivo Models

Gamma-oryzanol (ORY), found in rice (<i>Oryza sativa</i> L.), is a mixture of ferulic acid esters with triterpene alcohols, well-known for its antioxidant and anti-inflammatory properties. Our past research demonstrated its positive impact on cognitive function in adult mice, influencing synaptic plasticity and neuroprotection. In this study, we explored whether ORY can exert neuro-differentiating effects by using different experimental models. For this purpose, chemical characterization identified four components that are most abundant in ORY. In human neuroblastoma cells, we showed ORY's ability to stimulate neurite outgrowth, upregulating the expression of GAP43, BDNF, and TrkB genes. In addition, ORY was found to guide adult mouse hippocampal neural progenitor cells (NPCs) toward a neuronal commitment. Microinjection of ORY in zebrafish Tg (<i>-3.1 neurog1</i>:GFP) amplified <i>neurog1</i>-GFP signal, <i>islet1</i>, and <i>bdnf</i> mRNA levels. Zebrafish <i>nrf2a</i> and <i>nrf2b</i> morphants (MOs) were utilized to assess ORY effects in the presence or absence of Nrf2. Notably, ORY's ability to activate <i>bdnf</i> was nullified in <i>nrf2a-MO</i> and <i>nrf2b-MO</i>. Furthermore, computational analysis suggested ORY's single components have different affinities for the Keap1-Kelch domain. In conclusion, although more in-depth studies are needed, our findings position ORY as a potential source of bioactive molecules with neuro-differentiating potential involving the Nrf2 pathway.