NeuralCipher Research overview
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This study is the first to comprehensively explore both intracellular and computational mechanisms through which Neuropeptide S (NPS) protects against paraquat-induced dopaminergic toxicity in a Parkinson's disease (PD)-like SH-SY5Y cell model. Paraquat induces oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, mimicking key PD features. Bioinformatic analyses, including Reactome pathway mapping and molecular docking, confirmed a high-affinity interaction between NPS and its receptor NPSR1, activating GPCR-associated signaling. NPS treatment restored intracellular dopamine and ATP levels and increased tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT) expression. Cell viability was assessed using the MTT assay, while dopamine levels were measured via LC-MS/MS. p-ERK1/2, total ERK1/2, and Nrf2 were quantified by ELISA and western blot. Oxidative stress markers, including TBARS, MAO-A, MAO-B, and COMT, were analyzed by ELISA. Gene expression of Bax, Bcl-2, Caspase-3, Caspase-8, DAT, and VMAT was evaluated by qRT-PCR. TH, c-Fos, and NPSR1 were visualized using immunofluorescence. NPS significantly improved cell viability and restored ATP levels compromised by paraquat exposure. It also reduced TBARS, MAO-B, and COMT levels, reversed paraquat-induced ERK1/2 phosphorylation, and restored Nrf2 and MAO-A expression. Additionally, NPS upregulated the anti-apoptotic marker Bcl-2. Most of these protective effects were abolished in the presence of the NPSR antagonist ML154, indicating a receptor-mediated mechanism of action. In conclusion, NPS was found to attenuate oxidative stress, support mitochondrial and dopaminergic function, and influence apoptosis-related signaling in our cellular model. These findings suggest that targeting the NPS/NPSR1 system may hold therapeutic potential in neurodegenerative diseases such as PD, warranting further in vivo validation.
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