Rotenone-Induced Apoptosis Is Mediated By p38 And JNK MAP Kinases In Human Dopaminergic SH-SY5Y Cells

Abstract

Rotenone is a naturally derived pesticide that has recently been shown to evoke the behavioral and pathological symptoms of Parkinson's disease in animal models. Though rotenone is known to be an inhibitor of the mitochondrial complex I electron transport chain, little is known about downstream pathways leading to its toxicity. We used human dopaminergic SH-SY5Y cells to study mechanisms of rotenone-induced neuronal cell death. Our results suggest that rotenone, at nanomolar concentrations, induces apoptosis in SH-SY5Y cells that is caspase-dependent. Furthermore, rotenone treatment induces phosphorylation of c-Jun, the c-Jun N-terminal protein kinase (JNK), and the p38 mitogen activated protein (MAP) kinase, indicative of activation of the p38 and JNK pathways. Importantly, expression of dominant interfering constructs of the JNK or p38 pathways attenuated rotenone-induced apoptosis. These data suggest that rotenone induces apoptosis in the dopaminergic SH-SY5Y cells that requires activation of the JNK and p38 MAP kinases and caspases. These studies provide insights concerning the molecular mechanisms of rotenone-induced apoptosis in neuronal cells.

Meloxicam protects cell damage from 1-methyl-4-phenyl pyridinium toxicity via the phosphatidylinositol 3-kinase/Akt pathway in human dopaminergic neuroblastoma SH-SY5Y cells

“…Rotenone-induced neuronal death in SH-SY5Y cells is also attenuated by genetic suppression of JNK or p38 pathway (Newhouse et al, 2004). From the above findings, we formulated the following hypothesis ( …”

Protective effect of Bu-7, a flavonoid extracted from Clausena lansium, against rotenone injury in PC12 cells

“…The activation of JNK and p38 were reported to be responsible for p53-dependent apoptosis including the inhibition of the anti-apoptotic Bcl-2 protein, which further promoted the caspase process, which had a general role in rotenone-induced apoptosis in neuronal cells [30] . It was observed in SH-SY5Y cells that rotenone induced apoptosis through the activation of the JNK and p38 signaling pathways, which indicated their role in neuronal apoptosis [31][32][33][34] . Our results showed that rotenone (1 μmol/L) induced the phosphorylation of JNK and p38 after treatment for 24 h. Bu-7 pretreatment inhibited the rotenone-induced phosphorylation of both JNK and p38 and decreased the p53 level that was increased by rotenone.…”

Basic Fibroblast Growth Factor Protects against Rotenone-Induced Dopaminergic Cell Death through Activation of Extracellular Signal-Regulated Kinases 1/2 and Phosphatidylinositol-3 Kinase Pathways

“…Because it is lipophilic, rotenone crosses the blood-brain barrier readily. Because rotenone induces apoptotic cell death in cultured dopaminergic cells (King et al, 2001;Wang et al, 2002;Newhouse et al, 2004), it provides another useful model to study Parkinson's disease. However, mechanisms for rotenone-induced dopaminergic cell death have not been completely defined.…”