RIPK1 inhibitor ameliorates the MPP+/MPTP-induced Parkinson's disease through the ASK1/JNK signalling pathway

Receptor-interacting protein kinase 1 (RIPK1) is up-regulated in patients with neurodegenerative diseases. Our study aimed to explore the underlying mechanisms that involved in the neurotoxic function of RIPK1 in Parkinson's disease (PD). MPP+/MPTP-induced PD cellular and mice models were used in this study. The results showed that RIPK1 was high expressed and activated in MPP+-treated SH-SY5Y cells and MPTP-induced PD mice. Overexpression of RIPK1 facilitated cell apoptosis, necrosis, inflammation response, ROS production and mitochondrial dysfunction in MPP+- treated SH-SY5Y cells, while the RIPK1 inhibitor Nec-1s has an opposite effect. In addition, the Apoptosis-signaling kinase-1 (ASK1)/c-Jun N-terminal kinase (JNK) signalling pathway was activated during the overexpression of RIPK1, and inhibiting the ASK1/JNK signal by the ASK1 inhibitor partially reversed the decline of cell viability, the increase of cell apoptosis, necrosis and inflammation induced by RIPK1 overexpression in MPP+-treated SH-SY5Y cells. Further studies suggested that the inhibition of RIPK1 by Nec-1s largely alleviated the behavioural impairment in PD mice. Hence, our study indicated that the RIPK1 inhibitor Nec-1s has neuroprotective effects against PD through inactivating the ASK1/JNK signalling pathway.

Automated summary

RIPK1 is up-regulated in patients with neurodegenerative diseases, especially in Parkinson's disease. The study found that overexpression of RIPK1 leads to cell apoptosis, necrosis, inflammation, ROS production, and mitochondrial dysfunction, while inhibition of RIPK1 by Nec-1s has neuroprotective effects by deactivating the ASK1/JNK signaling pathway in PD. Further research is needed to explore the potential therapeutic implications of targeting RIPK1 in treating neurodegenerative diseases.