Glutamate-mediated oxidative stress causes neuronal cell death by increasing intracellular Ca2+ uptake, reactive oxidative species (ROS) generation, mitogen-activated protein kinase (MAPK) activation, and translocation of apoptosis-inducing factor (AIF) to the nucleus. In the current study, we demonstrated that corydaline exerts potent neuroprotective effects against glutamate-induced neurotoxicity. Treatment with 5 mmol/L glutamate increased cellular Ca2+ influx, ROS generation, MAPK activation, and AIF translocation. In contrast, corydaline treatment decreased cellular Ca2+ influx and ROS generation. Western blot analysis revealed that glutamate-mediated MAPK activation was attenuated by corydaline treatment. We further demonstrated that corydaline treatment inhibited the glutamate-mediated translocation of AIF to the nucleus. We propose that corydaline is a promising lead structure for the development of safe and effective neuroprotectants.

Calbindin-D28k is a calcium-binding protein that mediates intracellular calcium concentrations and exerts a neuroprotective effect against ischemic injury. Ferulic acid provides a neuroprotective effect against focal cerebral ischemia through its anti-oxidative and anti-inflammatory mechanisms. In this study, we investigated whether ferulic acid regulates calbindin-D28k expression during focal cerebral ischemia and glutamate treatment-induced neuronal cell death. Middle cerebral artery occlusion (MCAO) was performed to induce focal cerebral ischemia. Ferulic acid (100 mg/kg, i.v.) or vehicle was immediately administered after MCAO, and brain tissues were isolated 24 h after MCAO. RT-PCR and Western blot analyses showed a decrease in calbindin-D28k in MCAO-operated animals. We found that ferulic acid treatment prevented the MCAO-induced decrease in calbindin-D28k expression. Glutamate exposure elevated the intracellular calcium levels in cultured hippocampal cells, and ferulic acid prevented the glutamate exposure-induced increase in calcium levels. Moreover, ferulic acid also attenuated the glutamate toxicity-induced decrease in calbindin-D28k. Taken together, these in vivo and in vitro results demonstrate that ferulic acid regulates calbindin-D28k expression in neuronal cell injury. Therefore, these findings suggest that ferulic acid exerts a neuroprotective effect by modulating calbindin-D28k expression.