Neuroprotective effect of short-chain fatty acids against oxidative stress-induced SH-SY5Y injury via GPR43-dependent pathway

Abstract

A neurodegenerative disorder is a condition that causes a degeneration of neurons in the central nervous system, leading to cognitive impairment and movement disorders. An accumulation of oxidative stress in neurons contributes to the pathogenesis of neurodegenerative disorders. Over the past few years, several studies have suggested that short-chain fatty acids, metabolites of the gut microbiota, might have a beneficial effect in neurodegenerative disorders. A G protein-coupled receptor 43 (GPR43) plays an important role in modulating oxidative stress and inflammatory processes in several tissues. Interestingly, the downstream signaling pathways activated by GPR43 to modulate oxidative stress differ among tissues. Moreover, the cellular mechanisms underlying GPR43 activation in neuronal cells to handle oxidative stress remain unclear. In this present study, we tested the role of GPR43, which is activated by short-chain fatty acids or a specific GPR43 agonist, in an oxidative stress-induced neuronal cell line (SH-SY5Y) injury. Our findings suggest that a combination of short-chain fatty acids with a physiological function could protect neurons from H₂ O₂ -induced cell damage. The effect of short-chain fatty acids mixture was abolished by pretreatment with a GPR43 antagonist, indicating this protective effect is a GPR43-dependent mechanism. In addition, a specific GPR43 agonist shows a similar result to that found in short-chain fatty acids mixture. Furthermore, our findings indicate that the downstream activation of GPR43 to protect against oxidative stress-induced neuronal injury is a biased G_q activation signaling of GPR43, which results in the prevention of H₂ O₂ -induced neuronal apoptosis. In conclusion, our results show new insight into the cellular mechanism of GPR43 and its neuroprotective effect. Taken together, this newly discovered finding suggests that activation of the biased G_q signaling pathway of GPR43 might be a potential therapeutic target for aging-related neurodegeneration.

Keywords: G protein-coupled receptor 43; aging; calcium; neurodegeneration; short-chain fatty acids.