Induction of endoplasmic reticulum stress and JNK-dependent neuronal cell death by bupropion

초록

Endoplasmic reticulum (ER) provides a contained environment for the synthesis and proper folding of cellular proteins. Conditions adversely affecting ER protein folding result in the accumulation of unfolded or misfolded proteins in the ER lumen, a condition defined as ER stress. Cells with mild or transient stress switch on unfolded protein response (UPR)-associated signal transduction events to reestablish normal ER function. However, when the primary insult causing protein unfolding in the ER is protracted or excessive, cell death is induced, typically through apoptosis. Bupropion is a dopamine reuptake inhibitor and is used for treatment of depression and for smoking cessation. Although dopamine in synaptic cleft is dangerous to neuron, it is not known the effects of bupropion on ER stress-associated cellular injury. Here, we investigated the toxic mechanisms of bupropion in SH-SY5Y catecholaminergic cells. When cells treated with bupropion, dose-dependent cell death was observed. In addition, bupropion (100 g/mL) activated ER stress-associated signaling pathway, such as phsophorylation of eukaryotic initiation factor 2-alpha (eIF-2), JNK and p38-MAPK. The activated ER stress response was likely to be associated with apoptosis (activation of caspase-3 and induction of CHOP). Bupropion-induced cell death was inhibited by JNK-specific inhibitor, SP600125 (1 M). In conclusion, the relative high concentration of bupropion induced ER stress response and neuronal cell death, and the cytotoxicity of bupropion was partially dependent on JNK. Since the bupropion-induced catecholaminergic cell death may be associated with dopaminergic neurodegeneration, such as Parkinson’s disease, further in vivo study should be conducted to elucidate the clinical meanings of current study.