Rosmarinic acid ameliorated oxidative stress, neuronal injuries, and mitochondrial dysfunctions mediated by polyglutamine and ɑ-synuclein in Caenorhabditis elegans models

Numerous natural antioxidants have been developed into agents for neurodegenerative diseases (NDs) treatment. Rosmarinic acid (RA), an excellent antioxidant, exhibits neuroprotective activity, but its anti-NDs efficacy still reminds puzzled. Here, Caenorhabditis elegans models were employed to systematically reveal RA-mediated mechanisms in delaying NDs from diverse facets, including oxidative stress, the homeostasis of neural and protein, and mitochondrial disorders. Firstly, RA significantly inhibited reactive oxygen species accumulation, reduced peroxide malonaldehyde production, and strengthened the antioxidant defense system via increasing superoxide dismutase activity. Besides, RA activated Notch and Wnt signaling to promote neurohomeostasis, reduce neuronal loss, and ameliorated polyglutamine and ɑ-synuclein-mediated dyskinesia in NDs models. Further, RA enhanced proteostasis by activating insulin/insulin-like growth factor 1 signaling, mitogen activated protein kinases and heat-shock factor 1 pathways. More importantly, molecular docking results revealed that RA specifically bound huntington protein and ɑ-synuclein to prevent toxic protein aggregation, which was consistent with the data that RA diminished polyglutamine and ɑ-synuclein aggregates in nematodes. Finally, RA ameliorated mitochondrial dysfunction including increasing adenosine triphosphate and mitochondrial membrane potential levels and rescuing mitochondrial membrane proteins’ expressions and mitochondrial structural abnormalities via regulating mitochondrial dynamics genes and improving the mitochondrial kinetic homeostasis. Thus, this study systematically revealed the RA-mediated neuroprotective mechanism and promoted RA as a promising nutritional intervention strategy to prevent NDs.