Discovery of Potential Leonurine-Based Therapeutic Lead MJ210 Attenuates Parkinson's Disease Pathogenesis via NF-κB and MAPK Pathways: Mechanistic Insights from In Vitro and In Vivo Rotenone Models

Abstract

Parkinson's disease (PD) is a common neurodegenerative disease affecting motor and non-motor functions, with no effective treatment yet discovered. Neuroprotective compounds, both natural and synthetic, show promise but face challenges such as crossing the blood-brain barrier, limited serum stability, and higher toxicity. To tackle these obstacles, we have devised an innovative design strategy inspired by the neuroprotective properties of Leonurine, widely utilized in managing neurological disorders. Through rigorous screening of our compound library, we have identified a potent therapeutic molecule (MJ210) that exhibited remarkable efficacy in bolstering neuroprotection against rotenone-induced PD models, both in vitro and in vivo. Our findings revealed that administering MJ210 significantly increased neuronal survival in the SH-SY5Y model of PD. This was achieved by preventing apoptosis, reducing reactive oxygen species, mitigating mitochondrial dysfunction, and dampening neuroinflammation via ERK1/2-P38-JNK and P65-NFκB signaling pathways. In addition, MJ210 demonstrated remarkable neuroprotective abilities in vivo by significantly enhancing dopamine biosynthesis, alleviating motor dysfunction, improving balance and coordination, and reversing depression in rotenone-induced PD rats, even outperforming L-DOPA, the current gold standard treatment for PD. Therefore, MJ210 emerges as a significantly promising therapeutic candidate for PD, offering the potential for managing both the severity and progression of this disease.