The omega‐6 fatty acid derivative 15‐deoxy‐Δ 12,14 ‐prostaglandin J2 is involved in neuroprotection by enteric glial cells against oxidative stress

• Published in: The Journal of physiology Vol. 590; no. 11; pp. 2739 - 2750
• Main Authors: Abdo, Hind, Mahé, Maxime M., Derkinderen, Pascal, Bach‐Ngohou, Kalyane, Neunlist, Michel, Lardeux, Bernard
• Format: Journal Article
• Language: English
• Published: 01.06.2012
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2011.222935

Key points Enteric glial cells play a major role in the regulation of enteric neuronal functions. 15‐Deoxy‐Δ 12,14 ‐prostaglandin J2 (15d‐PGJ2) is an omega‐6 fatty acid derivative that was recently identified as a novel glial‐derived mediator involved in the control of the proliferation and differentiation of intestinal epithelial cells. In this study, we show that 15d‐PGJ2 has neuroprotective properties during oxidative stress in the enteric nervous system. We furthermore show that 15d‐PGJ2 neuroprotective effects are dependent on the activation of the Nrf2 pathway and are associated with an increase of glutathione synthesis in neurons. This study supports the concept that omega‐6 derivatives might be used in preventive and/or therapeutic strategies for the treatment of enteric neuropathies. Abstract  Increasing evidence suggests that enteric glial cells (EGCs) are critical for enteric neuron survival and functions. In particular, EGCs exert direct neuroprotective effects mediated in part by the release of glutathione. However, other glial factors such as those identified as regulating the intestinal epithelial barrier and in particular the omega6 fatty acid derivative 15‐deoxy‐Δ 12,14 ‐prostaglandin J2 (15d‐PGJ2) could also be involved in EGC‐mediated neuroprotection. Therefore, our study aimed to assess the putative role of EGC‐derived 15d‐PGJ2 in their neuroprotective effects. We first showed that pretreatment of primary cultures of enteric nervous system (ENS) or human neuroblastoma cells (SH‐SY5Y) with 15d‐PGJ2 dose dependently prevented hydrogen peroxide neurotoxicity. Furthermore, neuroprotective effects of EGCs were significantly inhibited following genetic invalidation in EGCs of the key enzyme involved in 15d‐PGJ2 synthesis, i.e. L‐PGDS. We next showed that 15d‐PGJ2 effects were mediated by an Nrf2 dependent pathway but were not blocked by PPARγ inhibitor (GW9662) in SH‐SY5Y cells and enteric neurons. Finally, 15d‐PGJ2 induced a significant increase in glutamate cysteine ligase expression and intracellular glutathione in SH cells and enteric neurons. In conclusion, we identified 15d‐PGJ2 as a novel glial‐derived molecule with neuroprotective effects in the ENS. This study further supports the concept that omega‐6 derivatives such as 15d‐PGJ2 might be used in preventive and/or therapeutic strategies for the treatment of enteric neuropathies.