Open AccessSimvastatin Induces Neuroprotection in 6‐ OHDA ‐Lesioned PC 12 via the PI 3K/ AKT /Caspase 3 Pathway and Anti‐Inflammatory Responses
Author(s) -
Xu YunQi,
Long Ling,
Yan JunQiang,
Wei Lei,
Pan MengQiu,
Gao HuiMin,
Zhou Peng,
Liu Mei,
Zhu CanSheng,
Tang BeiSha,
Wang Qing
Publication year - 2013
Publication title -
cns neuroscience and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 69
eISSN - 1755-5949
pISSN - 1755-5930
DOI - 10.1111/cns.12053
Subject(s) - simvastatin , neuroprotection , pi3k/akt/mtor pathway , ly294002 , protein kinase b , pharmacology , downregulation and upregulation , chemistry , caspase 3 , dopaminergic , medicine , signal transduction , apoptosis , endocrinology , dopamine , biochemistry , programmed cell death , gene
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 .