Glucagon-like peptides 1 and 2 and vasoactive intestinal peptide are neuroprotective on cultured and mast cell co-cultured rat myenteric neurons

Ulrikke Voss,Eva Ekblad,Elin Sand,Per M Hellström

doi:10.1186/1471-230x-12-30

Ulrikke Voss, Eva Ekblad + Show 2 more

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https://doi.org/10.1186/1471-230x-12-30

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Journal: BMC gastroenterology	Publication Date: Apr 1, 2012
Citations: 60	License type: cc-by

Affiliation: Lund University, Uppsala University

Abstract

BackgroundNeuropathy is believed to be a common feature of functional and inflammatory intestinal diseases. Vasoactive intestinal peptide (VIP) is an acknowledged neuroprotective agent in peripheral, including enteric, and central neurons. The proglucagon-like hormones glucagon-like peptide 1 and 2 (GLP1 and GLP2) belong to the secretin/glucagon/VIP superfamily of peptides and GLP1 and GLP2 receptors are expressed in enteric neurons. Possible neuroprotective effects of these peptides were investigated in the present study.MethodsGLP1, GLP2 and VIP were added to cultured myenteric neurons from rat small intestine or to co-cultures of myenteric neurons and rat peritoneal mast cells. Receptor selectivity was tested by the simultaneous presence of a GLP1 receptor antagonist (exendin (9-39) amide) or a VIP receptor antagonist (hybrid of neurotensin 6-11 and VIP 7-28). Neuronal survival was examined using immunocytochemistry and cell counting.ResultsGLP1, GLP2 and VIP significantly and concentration-dependently enhanced neuronal survival. In addition the peptides efficiently counteracted mast cell-induced neuronal cell death in a concentration-dependent manner. Exendin(9-39)amide reversed GLP1-induced neuroprotection while GLP2- and VIP-induced enhanced neuronal survival were unaffected. The VIP receptor antagonist reversed GLP1- and VIP-induced neuroprotection while the GLP2-induced effect on neuronal survival was unaffected.ConclusionsBy activating separate receptors VIP, GLP1 and GLP2 elicit neuroprotective effects on rat myenteric neurons cultured with or without mast cells. This implies a powerful therapeutic potential of these peptides in enteric neuropathies with a broad spectrum of applications from autoimmunity to functional disorders.

Highlights

Neuropathy is believed to be a common feature of functional and inflammatory intestinal diseases
Myenteric neurons in culture and in co-culture with mast cells Neurons cultured for 4 + 2 days stained well with both human neuronal proteins HuC and HuD (HuC/HuD) and PGP9.5 and were uniformly dispersed throughout the culture wells
Addition of mast cells to pre-cultured (4 days in vitro (DIV)) myenteric neurons resulted in a disintegrated nerve fibre network and a markedly enhanced loss of nerve cell bodies (Figure 1B)

Summary

Introduction

Neuropathy is believed to be a common feature of functional and inflammatory intestinal diseases. The pathogenesis of GI symptoms in diabetes is not fully understood but autonomic neuropathy and abnormal glucose levels are Glucagon-like peptide 1 (GLP1) attracts much attention due to its effects on glucose-stimulated insulin secretion, beta-cell proliferation and food intake. It is currently in clinical use in patients with type II diabetes in order to treat hyperglycemia and a number of beneficial side effects e.g. weight loss due to better satiety control [for a recent review see [6]] and protection of beta-cells against cytokine-mediated apoptosis [7] have been recognized. In this context it is of interest to note that GLP1 given to patients with irritable bowel syndrome provides an effective, on demand, relief of acute pain attacks [12]

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