A substance P mediated pathway contributes to 6-hydroxydopamine induced cell death

The neurotoxin 6-hydroxydopamine (6-OHDA) is used to induce dopaminergic cell death, resulting in insufficient striatal dopamine content in the basal ganglia and motor dysfunction typical of Parkinson's disease. Dopamine induces release of the neuropeptide substance P (SP) within the substantia nigra, whereas SP is able to potentiate striatal dopamine release, thus creating a positive feedback mechanism. Previous studies, however, have shown that elevated SP is detrimental to neuronal survival and motor function in acute brain injury. In the current study, we demonstrate that 6-OHDA increases SP production in meso-striatal organotypic co-culture. Moreover, there was a significant correlation between SP content and lactate dehydrogenase release, a marker of cell death, suggesting elevated SP production may contribute to 6-OHDA induced cell death in vitro.