TRPM8 activation inhibits neuroinflammation and ameliorates neurodegeneration by modulating Nrf2/HO-1 and NF-κB pathways in vivo and in vitro.

Neuroinflammation plays a pivotal role in the progression of Parkinson's disease (PD), and molecules capable of inhibiting neuroinflammation hold significant promise as therapeutic targets for PD. The transient receptor potential melastatin 8 (TRPM8), a transmembrane protein with well-documented anti-inflammatory properties, is prominently expressed in macrophages. This study marks the first exploration of the anti-PD effects of TRPM8 activation and its underlying mechanisms. Experimental results demonstrate that Icilin, a small-molecule TRPM8 agonist, conferred beneficial effects in a PD mouse model, including improved motor function, reduced dopaminergic neuronal damage, and suppressed neuroinflammation. Mechanistically, Icilin alleviated neuroinflammation in microglia through TRPM8 activation, which modulated the Nrf2/HO-1 and NF-κB pathways, thereby shielding neurons from microglia-mediated inflammatory injury. These findings not only underscore the therapeutic potential of TRPM8 in PD but also highlight its relevance to functional food science, as TRPM8 activation could be harnessed to develop dietary interventions with neuroprotective and anti-inflammatory properties. In conclusion, our study identifies TRPM8 as a promising therapeutic target for PD by regulating neuroinflammation via the Nrf2/HO-1 and NF-κB pathways, offering novel insights for the development of functional foods aimed at mitigating neurodegenerative diseases.