The recent development of new selective agonists and antagonists for estrogen receptor (ER) a-and b-mediated transcription has facilitated exploration of the role of classical ERs in the neuroprotective and neuroreparative mechanisms of estradiol, and has extended previous data obtained in ERa and ERb knockout mice. Both ERa and ERb seem to be involved in the neuroprotective actions of the hormone, although they mediate the activation of different mechanisms and affect different parameters. For instance, in experimental autoimmune encephalomyelitis, an ERa agonist was anti-inflammatory and exerted protection at the onset of the disease, whereas an ERb agonist was not anti-inflammatory but induced recovery from the disease [10].