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This suggested that the IGF\u20101 system is a central mechanism through which estrogen acts to protect the nigrostriatal DA system. Moreover, these results also suggest that IGF\u20101R\u2010induced intracellular signaling pathways are involved in the estrogen mechanism that promotes neuronal survival.<jats:italic>In vitro<\/jats:italic>, two convergent intracellular signaling pathways used by estrogen and IGF\u20101, the mitogen\u2010activated protein kinase (MAPK\/ERK), and phosphatidyl\u2010inositol\u20103\u2010kinase\/Akt (PI3K\/Akt), have been demonstrated to be neuroprotective. Continuous central infusions of MAPK\/ERK and PI3K\/Akt inhibitors were used to test the hypothesis that one or both of these signal transduction pathways mediates estrogen and\/or IGF\u20101 neuroprotection of SNpc DA neurons after a unilateral administration of 6\u2010OHDA into the MFB of rats. Motor behavior tests and tyrosine hydroxylase immunoreactivity revealed that the inhibitor of the PI3K\/Akt pathway (LY294002) blocked the survival effects of both estrogen and IGF\u20101, while an inhibitor of the MAPK\/ERK signaling (PD98059) was ineffective. Western blot analyses showed that estrogen and IGF\u20101 treatments increased PI3K\/Akt activation in the SN; however, MAPK\/ERK activation was decreased in the SN. Indeed, continuous infusions of inhibitors blocked phosphorylation of PI3K\/Akt and MAPK\/ERK. These findings indicate that estrogen and IGF\u20101\u2010mediated SNpc DA neuronal protection is dependent on PI3K\/Akt signaling, but not on the MAPK\/ERK pathway. \u00a9 2008 Wiley Periodicals, Inc. 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