Neurokinin receptor one agonist septide offers neuroprotection on dopaminergic neurons

Abstract

Parkinson’s disease is a serious motor disorder and it is caused by a degeneration of dopaminergic neurons in the substantia nigra pars compacta. Neurokinins (NK) are a group of neuropeptides that are suggested to be involved in the pathogenesis of Parkinson’s disease. Functions of NKs are mediated by NK receptors. Substance P, the natural ligand of NK1 receptor, is found to have neuroprotective effects on dopaminergic neurons. Septide is a selective NK1 receptor agonist. In order to investigate the neuroprotective effect of septide in vitro, septide (1 M) was co-incubated with 6-hydroxydopamine (6-OHDA, 200 M) in primary cell cultures of neonatal rat dopaminergic neurons. After 25 h, massive neuronal cell death was observed in those cultures incubated with 6-OHDA, whereas in septide co-incubation cultures most neurons were seen to be intact. By flow cytometric analysis, 17.03 8 2.13% of tyrosine hydroxylase (TH)-immunoreactive neurons were found to survive after co-incubation treatment but only 4.92 8 1.40% of TH-positive neurons were found to survive after 6- OHDA treatment. In addition, double immunofluorescence revealed that the level of TH immunoreactivity was also reduced in the surviving neurons after 6-OHDA treatment. No significant reduction of TH immunoreactivity was found in neurons co-incubated with septide and 6-OHDA. The present results indicate that septide has neuroprotective effects on dopaminergic neurons in culture. In addition, in rat model of Parkinson’s disease, neuroroprotective effects on dopaminergic neurons were also observed. Activation of NK1 receptor by septide may have implications in treatment of Parkinson’s disease. Acknowledgement: The present work was supported by Joint Research Scheme, National Natural Science Foundation of China and Research Grants Council of Hong Kong, 30218002 and N_HKBU202/02.