Simvastatin Induces Neuroprotection in 6‐ OHDA ‐Lesioned PC 12 via the PI 3K/ AKT /Caspase 3 Pathway and Anti‐Inflammatory Responses

摘要

Summary Background In addition to their original applications for lowering cholesterol, statins display multiple neuroprotective effects. Inflammatory reactions and the PI 3K/ AKT /caspase 3 pathway are strongly implicated in dopaminergic neuronal death in P arkinson's disease ( PD ). This study aims to investigate how simvastatin affects 6‐hydroxydopamine‐lesioned PC 12 via regulating PI 3K/ AKT /caspase 3 and modulating inflammatory mediators. Methods 6‐hydroxydopamine‐treated PC 12 cells were used to investigate the neuroprotection of simvastatin, its association with the PI 3K/ AKT /caspase 3 pathway, and antiinflammatory responses. Dopamine transporters ( DAT ) and tyrosine hydroxylase ( TH ) were examined in 6‐hydroxydopamine‐treated PC 12 after simvastatin treatment. Results Simvastatin‐mediated neuroprotection was associated with a robust reduction in the upregulation induced by 6‐ OHDA of inflammatory mediators including IL ‐6, COX 2, and TNF ‐α. The downregulated DAT and TH levels in 6‐ OHDA ‐lesioned PC 12 were restored after simvastatin treatment. Simvastatin reversed 6‐ OHDA ‐induced downregulation of PI 3K/Akt phosphorylation and attenuated 6‐ OHDA ‐induced upregulation of caspase 3 in PC 12. Furthermore, the PI 3K inhibitor LY 294002 pronouncedly abolished the simvastatin‐mediated attenuation in caspase 3. Conclusions Our results demonstrate that simvastatin provides robust neuroprotection against dopaminergic neurodegeneration, partially via antiinflammatory mechanisms and the PI 3K/Akt/caspase 3 pathway. These findings contribute to a better understanding of the critical roles of simvastatin in treating PD and might elucidate the molecular mechanisms of simvastatin effects in PD .