Statins

Neurorestorative Treatments for Traumatic Brain Injury

Statins, inhibitors of cholesterol biosynthesis used to lower cholesterol levels, induce angiogenesis, neurogenesis and synaptogenesis, and enhance functional recovery following TBI in rats (Lu et al., 2004a; Lu et al., 2004b; Lu et al., 2007b; Wu et al., 2008b). These beneficial effects of statins are independent of cholesterol-lowering action. Beneficial effects of simvastatin may be mediated through activation of Akt, Forkhead transcription factor 1 and nuclear factor–κB signaling pathways, which suppress the activation of caspase-3 and apoptotic cell death, and thereby, lead to neuronal function recovery after TBI (Wu et al., 2008a). Simvastatin activates the Akt-mediated signaling pathway, subsequently upregulating the expression of growth factors and inducing neurogenesis in the dentate gyrus of the hippocampus, thereby leading to restoration of cognitive function after TBI in rats (Wu et al., 2008b). In addition, simvastatin treatment provided long-lasting (3 month) functional improvement following TBI in rats (Mahmood et al., 2009). The protective mechanisms of statins may be partly attributed to a reduction in the inflammatory response following TBI (Li et al., 2009). When administered in combination with MSCs in a rat model of TBI, atorvastatin increased MSC access and/or survival within the injured brain and enhanced functional recovery compared with either MSC or atorvastatin monotherapy (Mahmood et al., 2007a), suggesting that statins might be used in conjunction with MSC transplantation for treating neurological disorders and injuries.

Given the wide use, favorable safety profile and positive clinical data for statins, the rare occurrence of serious adverse events and the extensive available preclinical data demonstrating neuroprotection and neurorestoration (Wible and Laskowitz, 2010), further clinical trials are warranted to determine the neuroprotective and neurorestorative properties of statins following TBI. The effect of rosuvastatin on TBI-induced cytokine change is ongoing in a phase I/II trial (ClinicalTrials.gov, NCT00990028