Protective effect of conditioned medium derived from melatonin-stimulated stem cells from the apical papilla on glutamate-induced neurotoxicity in PC12 cells.

Glutamate-induced neurotoxicity can be attenuated via paracrine mechanisms involving mesenchymal stem cells (MSCs). Conditioned medium (CM) from dental MSCs stimulates neuroprotective effects through trophic factors, and melatonin is a known enhancer of the efficacy of conditional media. Here, we investigated the protective effect of CM derived from stem cells from the apical papilla (SCAPs), supplemented without and with melatonin CM (SCAP-CM and Mel-CM), against glutamate-induced PC12 cell apoptosis via the inhibition of intracellular calcium influx and reactive oxygen species (ROS) production. The results showed that CM effectively reduced glutamate-induced intracellular calcium ion concentration, ROS production, and LDH levels in PC12 cells, elevated mitochondrial membrane potential, and inhibited Bax and Cytochrome c protein expression while increasing Bcl-2 protein expression. Moreover, CM significantly reduced the expression of caspase-9 and caspase-3 to inhibit glutamate-induced PC12 cell apoptosis. Notably, Mel-CM outperformed SCAP-CM in all aspects. This study demonstrates that melatonin can enhance the paracrine effects of stem cells and that Mel-CM mediates neuroprotection by inhibiting neuronal cell damage and apoptosis induced by glutamate-induced neurotoxicity.