In the vast world of our body’s endocannabinoid system, there is a newly discovered hero: N-oleoylglycine (OlGly). OlGly, part of the endocannabinoidome (eCBome), has caught the attention of scientists for its potential protective effects against brain injuries. The eCBome is like a superhero league, with various members working together to keep our brain cells safe. However, OlGly’s influence on Parkinson’s disease (PD) wasn’t known until now. This study explores OlGly’s role in protecting neuroblastoma cells from PD-like damage caused by 1-methyl-4-phenyl-pyridinium (MPP+), a toxic compound. By activating a receptor called PPARα, OlGly shields the cells from harm and reduces inflammatory responses. The study’s findings suggest that OlGly might hold promise as a therapeutic agent for treating MPP+-induced neurotoxicity. Jump into the fascinating world of the endocannabinoidome and explore this groundbreaking research!

N-oleoylglycine (OlGly) is a lipid mediator that belongs to the expanded version of the endocannabinoid (eCB) system, the endocannabinoidome (eCBome), which has recently gained increasing attention from the scientific community for its protective effects in a mouse model of mild traumatic brain injury. However, the effects of OlGly on cellular models of Parkinson’s disease (PD) have not yet been investigated, whilst other lipoaminoacids have been reported to have beneficial effects. Moreover, the protective effects of OlGly seem to be mediated by direct activation of proliferator-activated receptor alpha (PPARα), which has already been investigated as a therapeutic target for PD. Therefore, this study aims to investigate the possible protective effects of OlGly in an in vitro model obtained by treating the neuroblastoma cell line, SH-SY5Y (both differentiated and not) with 1-methyl-4-phenyl-pyridinium (MPP+), which mimics some cellular aspects of a PD-like phenotype, in the presence or absence of the PPARα antagonist, GW6471. Our data show that MPP+ increases mRNA levels of PPARα in both non differentiated and differentiated cells. Using assays to assess cell metabolic activity, cell proliferation, and pro-inflammatory markers, we observed that OlGly (1 nM), both as treatment (1 h) and pre-treatment (4 h), is able to protect against neuronal damage induced by 24 h MPP+ exposure through PPARα. Moreover, using a targeted lipidomics approach, we demonstrate that OlGly exerts its effects also through the modulation of the eCBome. Finally, treatment with OlGly was able also to reduce increased IL-1β induced by MPP+ in differentiated cells. In conclusion, our results suggest that OlGly could be a promising therapeutic agent for the treatment of MPP+-induced neurotoxicity.

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