Systemic administration of erythropoietin (EPO) has been shown to reduce neuronal cell death and neurological dysfunction in animal models of stroke, epilepsy, head injury and multiple sclerosis (MS). It is has been hypothesized that the efficacy of EPO in animal models of MS may reflect an anti-inflammatory activity of this neuroprotective cytokine. Experiments performed on neuronal cell cultures indicate that the neuroprotective effects of EPO are associated with induction of anti-apoptotic genes such as hiap-1 and xiap that belong to the inhibitor of apoptosis (IAP) family. The neuroprotective effects of EPO may also result from suppression of the JNK stress-signaling pathway, which has been implicated in dopamine neuronal death in Parkinson's disease (PD). Consistent with this hypothesis, intracerebral administration of EPO reduces dopamine neuron loss in the MPTP pre-clinical model of PD. The primary objective of the present application is to determine whether systemic administration of EPO reduces dopamine neuron loss in inflammatory and neurotoxic models of PD by increasing the expression of xiap and hiap-1 in the nigrostriatal pathway. We will test this hypothesis by examining whether the neuroprotective effects of EPO are diminished in mice that lack xiap or hiap-1. Given that activation of the immediate-early gene c-Jun is thought to be a major signaling pathway that mediates dopamine neuron loss in animal models of PD, we will also determine whether conditional deletion of c-jun in nigrostriatal dopamine neurons of adult mice reduces the loss of these neurons following administration of the dopaminergic neurotoxin MPTP. We will also determine whether EPO is able to produce a further reduction of dopamine neuron loss in mice with a conditional deletion of c-jun in the nigrostriatal pathway. In order to determine whether EPO and IAP induction reduce dopamine neuron loss produced by brain inflammation, we will examine the neuroprotective effects of systemic EPO administration and virally-mediated IAP over-expression in rats that have received an intranigral injection of the pro-inflammatory bacterial toxin lipopolysaccharide. By determining whether systemic administration of EPO reduces the loss of nigrostriatal dopamine neurons in animal models of PD and the mechanisms by which this neuroprotective action occurs, we will address the therapeutic potential of this cytokine for PD.