Neuroprotective effect of muscone on glutamate-induced apoptosis in PC12 cells via antioxidant and Ca2+ antagonism

• We studied muscone-mediated neuroprotection using in vitro PC12 model.
• Muscone exerted neuroprotection against neurotoxicity induced by glutamate.
• Its neuroprotective effect is via preventing oxidative stress and Ca2+ influx.
• The study proved the novel evidence of its molecule mechanism.

In the pathogenesis of cerebral ischemia, glutamate excitotoxicity activates N-methyl-d-aspartate (NMDA) receptors which induce calcium influx and oxidative stress. Muscone exerts potent neuroprotective activities on cerebral ischemia. However, its underlying mechanism is yet to be elucidated. In this study, we demonstrated that pretreatment with muscone in PC12 cells markedly ameliorated the loss of cell viability, mitochondrial membrane potential (MMP) collapse, the release of lactate dehydrogenase (LDH), Ca2+ overload, reactive oxygen species (ROS) generation, and cell apoptosis induced by glutamate. Furthermore, muscone also decreased NR1 (NMDA receptor subunit 1) protein expression, the ratio of Bax/Bcl-2 protein expression and prevented activitation of Ca2+/calmodulin-dependent protein kinase type II (CaMKII) and ASK1/JNK/p38 signaling pathways elicited by glutamate in PC12 cells. In conclusion, our results provided novel evidence that muscone protected PC12 cells against glutamate-induced apoptosis by attenuating ROS generation and Ca2+ influx, via NR1 and CaMKII-depended ASK-1/JNK/p38 signaling pathways.