Neurokinin one (NK1) receptor is Substance P (SP) receptor and it is abundantly distributed in the basal ganglia. Growing evidences were shown on their possible roles in the pathogenesis and treatment of Parkinson's disease (PD). NK1 receptor is a kind of G-protein-coupled-receptor (GPCR) and it links to various downstream survival signaling pathways. In the present study, treatment of NK1 receptor agonist septide [(Pyr6, Pro9)-SP (6-11)] was found to ameliorate the motor deficit in 6-hydroxydopamine (6-OHDA) lesioned rats in apomorphine rotation test. Septide treatments were also demonstrated to provide neuroprotection. In 6-OHDA lesioned rats, protection of TH immunoreactive neurons and terminals in substantia nigra (SN) and striatum was found after septide treatment. In SH-SY5Y cultures, cytotoxicity of 6-OHDA was reduced by septide pretreatment. In addition, up-regulations of phosphorylated serine-threonine kinase Akt and phosphorylated mitochondrial apoptotic protein BAD were observed in both in vivo and in vitro models, indicating the inhibition of apoptotic pathway by septide. In conclusion, septide could trigger the pro-survival Akt/PKB signaling pathway and protect dopaminergic neurons in in vivo and in vitro models against 6-OHDA toxicity. Therefore septide treatment may have therapeutic implications in treatment of PD. Copyright © 2011 Elsevier Ltd. All rights reserved.