Synthetic Cyclic C5-Curcuminoids Increase Antioxidant Defense and Reduce Inflammation in 6-OHDA-Induced Retinoic Acid-Differentiated SH-SY5Y Cells

Parkinson's disease (PD) is recognized as one of the most common neurodegenerative disorders globally. The primary factor contributing to this condition is the loss of dopaminergic neurons, which results in both motor and nonmotor symptoms. The etiology of neurodegeneration remains unclear. However, it is characterized by the elevated production of reactive oxygen species, which subsequently leads to oxidative stress, lipid peroxidation, mitochondrial dysfunction, and inflammation. The investigation of the applicability of natural compounds and their derivatives to various diseases is becoming increasingly important. The possible role of curcumin from <i>Curcuma longa</i> L. and its derivatives in the treatment of PD has been partially investigated, but there are no data on the action of synthetic cyclic C₅-curcuminoids and chalcones tested in a Parkinson's model. Two chalcones and five synthetic cyclic C₅-curcuminoids with potential antioxidant properties were investigated in an in vitro model of 6-hydroxydopamine (6-OHDA)-induced neurodegeneration in differentiated SH-SY5Y cells. Reactive oxygen species (ROS) production, total antioxidant capacity, antioxidant enzyme activity, thiol and ATP levels, caspase-3 activity, and cytokine release were examined after treatment with the test compounds. Based on these results, one cyclic chalcone (compound <b>5</b>) and three synthetic cyclic C₅-curcuminoids (compounds <b>9</b>, <b>12</b>, and <b>13</b>) decreased oxidative stress and apoptosis in our in vitro model of neurodegeneration. Compounds <b>5</b> and <b>9</b> were also successful in decreasing the production of pro-inflammatory cytokines (IL-6, IL-8, and TNF-α), while promoting the release of anti-inflammatory cytokines (IL-4 and IL-10). These findings indicate that these two compounds exhibit potential antioxidant, anti-apoptotic, and anti-inflammatory properties, rendering them promising candidates for drug development.