Enteric glial cells protect neurons from oxidative stress in partviareduced glutathione

Abstract

Enteric glial cells (EGCs) are essential in the control of gastrointestinal functions. Although lesions of EGCs are associated with neuronal degeneration in animal models, their direct neuroprotective role remains unknown. Therefore, the aims of this study were to demonstrate the direct neuroprotective effects of EGCs and to identify putative glial mediators involved. First, viral targeted ablation of EGCs in primary cultures of enteric nervous system increased neuronal death both under basal conditions and in the presence of oxidative stress (dopamine, hydrogen peroxide). Second, direct or indirect coculture experiments of EGC lines with primary cultures of enteric nervous system or neuroblastoma cell lines (SH-SY5Y) prevented neurotoxic effects induced by oxidative stress (increased membrane permeability, release of neuronal specific enolase, caspase-3 immunoreactivity, changes in [Ca(2+)](i) response). Finally, combining pharmacological inhibition and mRNA silencing methods, we demonstrated that neuroprotective effects of EGCs were mediated in part by reduced glutathione but not by oxidized glutathione or by S-nitrosoglutathione. Our study identified the neuroprotective effects of EGCs via their release of reduced glutathione, extending their critical role in physiological contexts and in enteric neuropathies.-Abdo, H., Derkinderen, P., Gomes, P., Chevalier, J., Aubert, P., Masson, D., Galmiche, J.-P., Vanden Berghe, P., Neunlist, M., Lardeux, B. Enteric glial cells protect neurons from oxidative stress in part via reduced glutathione.

Emerging roles for enteric glia in gastrointestinal disorders

“…The functional consequences of this infection and whether or not the infected glia will go on to die remain to be determined. These findings are consistent with previous work showing that the enteric glia are preferentially infected with adenovirus in vitro (40) and suggest that viral infection of glia may lead to dysfunction and contribute to dysmotility.…”

Novel functional roles for enteric glia in the gastrointestinal tract

“…22 In neuron-glia co-cultures in vitro, the story is clearer and Abdo et al identified reduced glutathione and 15d-PGJ2 as factors secreted by enteric glial cells that protect neurons from oxidative stress. 71,72 Glial cell line-derived neurotrophic factor (GDNF) is also a prospective enteric glial-derived neuroprotective factor, 73 but the physiological significance of GDNF secretion by enteric glia is unclear. Transgenic overexpression of GDNF in glia was necessary for neuroprotective effects, 73 and GDNF expression is normally confined to smooth muscle cells and not enteric glia.…”

Enteric glia and neuroprotection: basic and clinical aspects

“…This suggests that EGCs are involved in the survival of enteric neurons. Furthermore, this study also showed that neuronal susceptibility to damaging factors such as oxidative stress (H 2 O 2 or dopamine) was enhanced as a result of EGC loss (1). Concerning soluble factors released by EGCs, in vitro and ex vivo data have demonstrated that reduced glutathione (GSH), but not oxidized glutathione or S-nitrosoglutathione, can prevent enteric neuronal cell death induced by H 2 O 2 .…”

“…Concerning soluble factors released by EGCs, in vitro and ex vivo data have demonstrated that reduced glutathione (GSH), but not oxidized glutathione or S-nitrosoglutathione, can prevent enteric neuronal cell death induced by H 2 O 2 . Selective genetic inhibition of glutamate cysteine ligase (the key enzyme of glutathione synthesis) in EGCs increased neuronal susceptibility to death induced by oxidative stress (1,40). Furthermore, EGC protective effects could also be due to their detoxification properties since they are able to take up glutamate or ␥-aminobutyric acid from an extracellular milieu by means of L-glutamate transporter (42) or ␥-aminobutyric acid transporter 2 (19), respectively.…”