The most prominent neurochemical hallmark of Parkinson's disease (PD) is the loss of nigrostriatal dopamine (DA). Animal models of PD have concentrated on depleting DA and therapies have focused on maintaining or restoring DA. Within this context estrogen protects against 6-hydroxdopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesions of the nigrostriatal DA pathway. Present studies tested the hypothesis that neuroprotective estrogen actions involve activation of the insulin-like growth factor-1 (IGF-1) system. Ovariectomized rats were treated with either a single subcutaneous injection of 17β-estradiol benzoate or centrally or peripherally IGF-1. All rats were infused unilaterally with 6-OHDA into the medial forebrain bundle (MFB) to lesion the nigrostriatal DA pathway. Tyrosine hydroxylase (TH) immunocytochemistry confirmed that rats injected with 6-OHDA had a massive loss of TH immunoreactivity in both the ipsilateral substantia nigra compacta (60% loss) and the striatum (>95% loss) compared to the contralateral side. Loss of TH immunoreactivity was correlated with loss of asymmetric forelimb movements, a behavioral assay for motor deficits. Pretreatment with estrogen or IGF-1 significantly prevented 6-OHDA-induced loss of substantia nigra compacta neurons (20% loss) and TH immunoreactivity in DA fibers in the striatum (<20% loss) and prevented the loss of asymmetric forelimb use. Blockage of IGF-1 receptors by intracerebroventricular JB-1, an IGF-1 receptor antagonist, attenuated both estrogen and IGF-1 neuroprotection of nigrostriatal DA neurons and motor behavior. These findings suggest that IGF-1 and estrogen acting through the IGF-1 system may be critical for neuroprotective effects of estrogen on nigrostriatal DA neurons in this model of PD. © 2003 Wiley-Liss, Inc.