HMG-CoA reductase inhibitors, commonly referred to as statins, have been shown to have a number of pleiotropic effects in addition to their ability to effectively lower cholesterol. Statin-induced neuroprotection has been paid special attention during recent years as researchers attempt to uncover the mechanisms underlying the protective effects. Since a reduction in cholesterol levels does not appear to be the cause of statins' neuroprotection, it has become necessary to explore alternative mechanisms. The results presented here reflect studies undertaken in an effort to determine the mechanism responsible for statin-induced neuroprotection. To better understand the molecular targets of statins in brain, DNA microarrays were used to identify gene expression patterns in the cerebral cortex of mice chronically treated with statins. Candidate genes identified from these studies were further examined and the anti-apoptotic protein Bcl-2 was chosen as the focus of the remaining studies. Long-term administration of simvastatin to primary neurons resulted in significant protection from cytotoxic insults coupled with an upregulation in Bcl-2 expression levels. Additional investigation using Bcl-2 inhibitors revealed that simvastatin-induced neuroprotection was dependent on the drug's ability to stimulate Bcl-2 expression. Examination of the protective effects provided evidence of a simvastatin-mediated reduction in apoptosis using caspase activation as a marker for apoptotic cell death. Results from ex vivo studies on dissociated brain cells from guinea pigs confirmed these findings and demonstrated the physiological importance of the simvastatin-mediated neuroprotection. Surprisingly, the neuroprotective actions of simvastatin appeared to be outside of its traditionally defined pathway, paving the way for future studies exploring alternative pathways for statin targeting. More work needs to be done to fully elucidate the mechanism of simvastatin-induced Bcl-2 upregulation. The work presented here lays the foundation for future studies of Bcl-2 stimulation by statins. Further investigation of this phenomenon could lead to advances in treating disorders in which excess cell death has been implicated.Experimental studies both in vitro and in vivo have reported that changes in cholesterol levels alter amyloid precursor protein ... Statins appear to reduce the risk of AD; however the mechanism underlying statin efficacy does not appear to beanbsp;...
|Title||:||Neuroprotection Induced by Simvastatin is Due to an Upregulation of the Anti-apoptotic Protein Bcl-2|
|Author||:||Leslie Ngozi Johnson|
|Publisher||:||ProQuest - 2006|