Selective damage to and protection of enteric neurons in vitro in models of ischemia and reperfusion
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Date
2014-08-21
Authors
Kearon, Joanne
Keyword
Enteric , Inflammation , Hypoxia , Neurons , GDNF , Ischemia , ENS , Reperfusion
Abstract
The dysregulation of motility typical in inflammatory bowel disease (IBD) indicates involvement of the enteric nervous system (ENS). Indeed, animal models of IBD have demonstrated that intestinal inflammation is typified by the early loss of enteric neurons. It has been proposed that ischemia may occur in intestinal inflammation, due to the organization of splanchnic circulation combined with local inflammatory damage. Therefore, we hypothesized that the ENS experiences ischemic challenge in inflammation, which we investigated by probing for hypoxia-inducible factor 1-α (HIF1-α) in the 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-model of colitis in adult rats. By Day 2 of TNBS-induced colitis, HIF1-α presence in the nuclei of myenteric neurons had significantly increased, indicating hypoxic challenge.
Despite the potential for ischemia to occur in inflammation, little is known about the impact of the resultant metabolic inhibition on enteric neurons. We further hypothesized that metabolic challenge would cause neuronal damage. Glucose deprivation, hypoxia and treatment with an electron transport chain (ETC) uncoupler caused neuron loss and axonal damage in in vitro co-cultures of myenteric neurons, intestinal smooth muscle cells and glia. Furthermore, we investigated the potential impact of subsequent reperfusion on myenteric neurons by resupplying glucose following a period of deprivation. Resupply of glucose was observed to cause acute neuron loss in vitro.
Lastly, if the ENS is damaged by ischemia and ischemia-reperfusion, it is then important to investigate methods of neuroprotection. In the CNS, glial cell line-derived neurotrophic factor (GDNF) and HIF1-α have both been demonstrated to be neuroprotective during metabolic inhibition. In co-cultures, GDNF was observed to prevent neuron loss by an ETC uncoupler or glucose deprivation. Hypoxic preconditioning also protected against neuron damage in a HIF1- α dependent manner. We concluded that the ENS is vulnerable to ischemia and ischemia-reperfusion occurring in inflammation. Further, GDNF and HIF1-α can be neuroprotective during metabolic challenge.