From Formulation to Function: γ‑Oryzanol Solid Dispersion Development and Its Neuroprotective Effects on the...

Major depressive disorder (MDD) is a prevalent psychiatric condition linked to suicide risk and public health impact. Current antidepressants often cause side effects and have delayed efficacy, driving interest in natural compounds with antioxidant properties as alternative treatments. γ-Oryzanol (GO) exhibits antioxidant, neuroprotective, and antidepressant properties that warrant investigation. However, its clinical application is restricted due to its water-insoluble properties, which lead to poor oral bioavailability. Therefore, this study aimed to develop a γ-oryzanol solid dispersion (GOSD) to improve GO water solubility. Then, its neuroprotective effects against dexamethasone-induced toxicity in SK-N-SH cells were evaluated to forge a clear link between the formulation and the function. The GOSD was successfully developed by using a solvent melting method. The developed GOSD could enhance the water solubility of GO up to 1.37 ± 0.05 mg/mL and enabled GO release under simulated intestinal conditions, indicating oral bioavailability improvement. In addition, the GOSD maintained good physical and chemical stability under a 6-month storage period at room temperature. Regarding the neuroprotective potential of the GOSD, our findings indicated that all tested concentrations were nontoxic to SK-N-SH cells. Interestingly, through the enhanced water solubility of GO, GOSD pretreatment demonstrated superior neuroprotective efficacy over free GO against dexamethasone-induced cytotoxicity. GOSD pretreatment prior to dexamethasone exposure significantly decreased abnormal and apoptotic cells by reducing ROS levels and increasing the SOD activity. Remarkably, GOSD pretreatment restored synaptic plasticity through multiple mechanisms: reducing MAO activity, suppressing GR expression, and upregulating synaptophysin expression. These results strongly support the GOSD as a safe and effective alternative therapeutic approach for treating depressive disorders.