In the current study, we demonstrate that intrastriatal 6-OHDA lesions result in elevated SP production within the ipsilateral SN that remained above sham levels for 21 days. The increased SP levels were associated with increased BBB permeability, microglial and astrocyte activation, increased dopaminergic cell death and profound motor deficits. Moreover, treatment with additional SP at the time of 6-OHDA administration accelerated the progression of the disease, with animals displaying profound motor deficits and exacerbated dopaminergic cell death. In contrast, blocking the effects of SP with administration of an NK1 antagonist preserved barrier integrity, reduced inflammatory Neferine processes, attenuated 6OHDA induced cell death and resulted in a significant improvement in motor function. To the best of our knowledge, this is the first demonstration that increased SP may play a critical role in early dopaminergic degeneration. Although a potential role for SP in PD has been previously suggested, unlike in the current study, this was on the basis of decreased SP content and NK1 Nitisinone receptors within the BG in both clinical and experimental models of PD. These reports of SP decline were in post-mortem PD tissue and in models that replicate the late stages of the disease. It is likely that the observed loss of SP under these conditions is a secondary effect of dopaminergic degeneration, due to the interruption to the positive feedback regulation between SP and DA. Indeed, a 90% decrease in striatal DA has reportedly been required to deplete SP content within the SN. In this study, nigral SP content was only decreased in the SP treated animals, which had significantly greater dopaminergic neuronal loss than any other group. There are several possible mechanisms to account for the increase in SP seen in this study. During early dopaminergic degeneration, DA production is upregulated from surviving neurons in an attempt to attenuate the loss of striatal DA. As mentioned, in the nigrostriatal pathway of the BG, SP and DA production are modulated by a positive feedback mechanism, whereby each neurotransmitter can potentiate the release of the other.