Statins exhibit neuroprotective effects after spinal cord injury (SCI). However, the molecular mechanism underlying these effects remains unknown. This study demonstrates that the hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin (Simv) exhibits neuroprotective effects on neuronal apoptosis and supports functional recovery in a rat SCI model by activating the Wnt/b-catenin signaling pathway. In specific, Simv administration after SCI significantly up-regulated the expression of low density lipoprotein receptor-related protein 6 phosphorylation and b-catenin protein, increased the mRNA expression of lymphoid enhancer factor-1 and T-cell factor-1, and suppressed the expression of b-catenin phosphorylation in the spinal cord neurons. Simv enhanced motor neuronal survival in the spinal cord anterior horn and decreased the lesion of spinal cord tissues after SCI. Simv administration after SCI also evidently reduced the expression levels of Bax, active caspase-3, and active caspase-9 in the spinal cord neurons and the proportion of transferase UTP nick end labeling (TUNEL)-positive neuron cells, but increased the expression level of Bcl-2 in the spinal cord neurons. However, the antiapoptotic effects of Simv were reduced in cultured spinal cord nerve cells when the Wnt/b-catenin signaling pathway was suppressed in the lipopolysaccharide-induced model. Furthermore, the Basso, Beattie, and Bresnahan scores indicated that Simv treatment significantly improved the locomotor functions of rats after SCI. This study is the first to report that Simv exerts neuroprotective effects by reducing neuronal apoptosis, and promoting functional and pathological recovery after SCI by activating the Wnt/b-catenin signaling pathway. Neural cell apoptosis influences the development of diseases in the central nervous system (CNS) and plays a significant part in the secondary injury of spinal cord injury (SCI), which influences the microglia and oligodendrocytes, as well as inhibits the recovery of white matter and neurological functions (Yuan and Yankner 2000;Beattie et al. 2002). Effective treatments remain lacking despite intensive research on SCI (Courtine et al. 2011). Simvastatin (Simv) is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor widely used to reduce cholesterol, and treat coronary heart disease and atherosclerosis (Mangili et al. 2014). Simv treatment also improves the conditions of patients with cancer, human rhabdomyosarcoma, Alzheimer's disease, rheumatoid arthritis, and traumatic CNS injury. However, these beneficial Received June 9, 2015; revised manuscript received September 3, 2015; accepted September 15, 2015.Address correspondence and reprint requests to Prof. Xifan Mei, Department of Orthopedics, First Affiliated Hospital of Liaoning Medical University, Jinzhou, China. E-mail: gaohaikai88@126.comAbbreviations used: APC, adenomatous polyposis coli; BBB, Basso, Beattie, and Bresnahan; CNS, central nervous system; DAPI, 4 0 ,6-diamidino-2-phenylindole; DMSO, dimethyl sulfoxide; GAPDH,...