Statins are widely used as medication to lower cholesterol levels in human patients. In addition, it was recently reported that they also reduce the incidence of stroke and progression of Alzheimer's disease when prophylactically administered. To date there is only limited information available on how statins exert this beneficial effect. In this study we investigated the neuroprotective effect of lovastatin in primary cortical neurons. We found that lovastatin protects cortical neurons in a concentration-dependent manner against glutamate-mediated excitotoxicity. Interestingly, lovastatin with or without glutamate and/or tumor necrosis factor-alpha (TNF-alpha) increased TNF receptor 2 (TNF-R2) expression in cortical neurons. It was previously shown that activation of TNF-R2 signaling, which includes phosphorylation of protein kinase B (PKB)/Akt and activation of nuclear factor-kappa B (NF-kappaB), protects neurons against ischemic or excitotoxic insults. To investigate if lovastatin-induced neuroprotection was mediated by TNF-R2 signaling, primary cortical neurons were isolated from TNF-R1(-/-) or TNF-R2(-/-) mice. We could show that lovastatin is neuroprotective in TNF-R1(-/-) neurons, while protection is completely absent in TNF-R2(-/-) neurons. Furthermore, lovastatin-mediated neuroprotection led to an increase in PKB/Akt and NF-kappaB phosphorylation, whereas inhibition of PKB/Akt activation entirely abolished lovastatin-induced neuroprotection. Thus, lovastatin-induced neuroprotection against glutamate-excitotoxicity via activation of TNF-R2-signaling pathways.