Muscone inhibits ferroptosis for neuroprotection in a Parkinson's disease model

Parkinson's disease (PD) is a common neurodegenerative disorder with no currently available effective treatments. Muscone is a bioactive compound extracted from musk, a widely used traditional Chinese medicine, that has demonstrated notable pharmacological properties and is considered beneficial for various models of neurological disorders. However, no studies have in vestigated the potential link between muscone and PD. This study tested the neuroprotective properties and mechanisms of muscone in a PD model. The behavioral findings revealed that muscone significantly improved motor deficits in PD mice while Cell Counting Kit-8 testing suggested that muscone substantially elevated cell viability in PD cellular models. Immunohistochemistry and Western blot analysis demonstrated that muscone alleviated the degeneration of dopamine neurons in PD model mice. Mechanistic studies revealed that muscone obstructs multiple routes of ferroptosis to alleviate symptoms of PD, indicating its potential to decrease iron accumulation, mitigate reactive oxygen species, inhibit lipid peroxidation, and augment antioxidant capacity. Moreover, bioinformatics study revealed that glycogen synthase kinase 3β (GSK-3β) is a vital target for muscone in the suppression of ferroptosis and is crucial in the treatment of PD. GSK-3β activity was significantly increased in both animal and cellular models of PD, while the expression of its principal downstream component, β-catenin, was diminished. However, muscone ameliorated these changes. Intracellular overexpression of GSK-3β subsequently nullified the protective effects of muscone on PD cell models and promoted ferroptosis in PD models by increasing iron levels, augmenting lipid peroxidation, and reducing antioxidant capacity. In conclusion, muscone can inhibit GSK-3β, alter ferroptosis, and confer protection against PD.