Cleistocalyx nervosum var. paniala seed extracts exhibit sigma-1 antagonist sensitive neuroprotective effects in PC12 cells and protect C. elegans from stress via the SKN-1/NRF-2 pathway

BACKGROUND: Cleistocalyx nervosum var. paniala (C. nervosum) is a plant that produces berries that are popular as a health food in Thailand. In previous studies we have identified C. nervosum fruit extracts to have anti-aging and anti-stress properties in C.elegans OBJECTIVE: Evaluate the neuroprotective properties of C. nervosum seed extracts and investigate the mechanisms behind their neuroprotective properties. METHODS: PC-12 cells were differentiated using NGF and treated with amyloid-β (Aβ)  (25–35)  creating a model of neurodegeneration, in which C. nervosum seed extracts were tested for neuroprotective properties. Cell viability was measured after 24 hours of using the MTT assay. We also measured the lifespan and “health span” of various C.elegans mutants and the wild type. RESULTS: C. nervosum seed extract protects PC12 cells from Aβ  (25–35)  toxicity, as well as potentiating NGF induced neurite outgrowth in the same cell line potentially under the control of the sigma-1 receptor. C. nervosum seed extracts have anti-aging properties in C. elegans, causing a significant increase in lifespan of Aβ expressing C. elegans and wild type worms. This appears to be regulated by SKN-1/NRF-2, possibly via the sigma-1 receptor. The DAF-16 pathway is also involved in the lifespan extension of C. elegans. CONCLUSIONS: C. nervousum has been often used as a functional food. We have shown its neuroprotective properties which are sensitive to sigma-1 receptor antagonism in PC12 cells, and involve the SKN-1/NRF-2 and DAF-16 pathway in C.elegans. Further research into the active compounds may lead to future drugs for preventing or treating neurodegenerative disease.