Statin-mediated Protective Effects in the Central Nervous System: General Mechanisms and Putative Role of Stress Proteins

Purpose: The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins", are used as cholesterol-lowering agents worldwide. This review, focused on recent experimental and clinical data, summarizes general mechanisms of statin actions underlying neuroprotective effects in the central nervous system (CNS) and presents evidence for putative mechanisms involving heat shock proteins and the survival-related PI-3K/Akt pathway that may be beneficial for the treatment of neurological disorders.

Methods: We carried out a medline search on statin actions, with respect to biochemical pathways and signal transduction on the one hand, and clinical studies in neurologic and retinal diseases on the other hand. Novel experimental data obtained in a rat model of axonal CNS injury were also included.

Results: Statins exert multiple effects on endothelial function, cell proliferation, inflammatory response, immunological reactions, platelet function, and lipid oxidation. These "pleiotropic actions" are independent of cholesterol lowering and appear to be beneficial in the context of brain injury. Several mechanisms of statin actions underlying neuroprotective effects may also involve heat shock proteins and the survival-related PI-3K/Akt pathway.

Conclusions: Available data suggest that statins may be of potential therapeutic use in a variety of diseases of the CNS including ischemic stroke, Alzheimer's disease, multiple sclerosis and some forms of retinal and eye diseases. Before general recommendations can be made and specific therapeutic approaches can be developed, more reliable clinical data and studies are required, and possible side effects must be carefully evaluated.