Statins and neuroprotection

(Statin-induced neuroprotection versus cell death)

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There is growing interest in the use of statins, HMG-CoA reductase inhibitors, for treating specific neurodegenerative diseases (e.g., cerebrovascular disease, Parkinson's disease, Alzheimer's disease, multiple sclerosis) and possibly traumatic brain injury. Neither is there a consensus on the efficacy of statins in treating the aforementioned diseases nor are the mechanisms of the purported statin-induced neuroprotection well-understood. Part of the support for statin-induced neuroprotection comes from studies using animal models and cell culture. Important information has resulted from that work but there continues to be a lack of progress on basic issues pertaining to statins and brain that impedes advancement in understanding how statins alter brain function. For example, there are scant data on the pharmacokinetics of lipophilic and hydrophilic statins in brain, statin-induced neuroprotection versus cell death, and statins and brain isoprenoids. The purpose of this mini-review will be to examine those aforementioned issues and to identify directions of future research.
Statins may be efficacious in preventing and treating certain neurodegenerative diseases and support is based in part on animal and cell culture studies. Further progress in understanding the mechanisms of statin-induced neuroprotection are hampered by a lack of fundamental data on actions of statins in the CNS. Three major topics which need to be addressed are the pharmacokinetics of lipophilic and hydrophilic statins in brain, cell protection versus cell death and regulation of brain isoprenoids. There is inadequate knowledge on each of these topics which we suggest has in some instances resulted in erroneous conclusions. For example, the notion that hydrophilic statins do not cross the blood-brain barrier is not supported by the limited data available. Basic studies are needed on statin transport in and out of brain as well as whether metabolism of statins occurs in the CNS. The issue of statin-induced cell protection versus cell death may simply be explainable by drug concentration but this issue requires further investigation. Regulation of brain FPP and GGPP are not understood. It is assumed that FPP and GGPP levels are reduced in brains of animals and neural cells treated with statins but there are no reported data. What is instructive is that the two recent studies reporting brain levels of FPP and GGPP in mice and humans found that GGPP was in greater abundance than FPP and isoprenoid levels were in the range of pmol to nmol. From a practical standpoint, those data have relevance to the procedure of examining effects of statins by adding back μmol amounts of FPP and/or GGPP in neural cells. Statins may be neuroprotective but efforts toward understanding the potential mechanisms will be enhanced by advancements in the CNS pharmacokinetics and pharmacodynamics of statins. More: interscience.wiley.com

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