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We demonstrate here in primary cultures of rat mesencephalic neurons that estrogen protects them from injury induced by conditioned medium obtained from lipopolysaccharide (LPS)\u2010activated microglia. LPS\u2010induced nitrite production and tumor necrosis factor\u2010\u03b1 up\u2010regulation in microglia were blocked by estrogen pretreatment. Estrogen neuroprotection was related to microglial activation of estrogen receptors (ERs), insofar as the protective effect of the microglia\u2010conditioned medium was overridden by pretreatment of microglia with the ER antagonist ICI 182,780. On the other hand, the specific ER\u03b1 antagonist, MPP dihydrochloride, only partially blocked the effects of estrogen, suggesting that estrogen protection was mediated via both ER\u03b1 and ER\u03b2. LPS treatment did not change ER\u03b1 mRNA levels in microglia, astrocytes, and neurons, but it up\u2010regulated ER\u03b2 mRNA levels in microglia and astrocytes. Similarly, increased ER\u03b2 protein levels were detected in LPS\u2010activated microglia. More interesting was that immunocytochemical analysis revealed that ER\u03b2 was localized in the cytoplasm of microglia and in the cell nucleus of astrocytes and neurons. In summary, our results support the notion that estrogen inhibits microglial activation and thus exhibits neuroprotective effects through both ER\u03b1 and ER\u03b2 activation. The cytoplasm location of microglial ER\u03b2 suggests the possible involvement of nonclassical effects of estrogen on microglia. Changes in microglial ER\u03b2 expression levels may modulate such effects of estrogen. \u00a9 2005 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.20583","type":"journal-article","created":{"date-parts":[[2005,7,12]],"date-time":"2005-07-12T18:20:13Z","timestamp":1121192413000},"page":"653-665","source":"Crossref","is-referenced-by-count":91,"title":["Estrogen provides neuroprotection against activated microglia\u2010induced dopaminergic neuronal injury through both estrogen receptor\u2010\u03b1 and estrogen receptor\u2010\u03b2 in 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