Antioxidants can function as powerful protectants for neurons in vitro. Here, the neuroprotective activity of lipophilic free radical scavengers synthetic (+/-) alpha-tocopherol (synthetic vitamin E) and natural (+) alpha-tocopherol (natural vitamin E) against oxidative stress was investigated and compared to the neuroprotective effect of the female sex hormone estradiol. Employing mouse clonal hippocampal HT22 cells and rat cerebellar granule neurons, we found that both types of alpha-tocopherol exerted a higher neuroprotective antioxidant activity than 17-beta estradiol. At concentrations as low as 100 nM, synthetic (+/-) alpha-tocopherol and natural (+) alpha-tocopherol protected neurons effectively against the oxidative cell death caused by the Alzheimer's disease-associated amyloid beta protein, hydrogen peroxide, and the excitatory amino acid glutamate. Moreover, vitamin E induced the activity of the redox-sensitive transcription factor NF-kappaB, which is involved in the control of nerve cell survival and, therefore, may play also a role in vitamin E-induced neuroprotection. These results may have implications regarding the prevention and treatment of oxidative stress-related degenerative disorders such as Alzheimer's disease.