The enteric nervous system (ENS) is pivotal in the regulation and coordination of gastrointestinal (GI) motility, secretion and blood flow. GI discomfort such as nausea, bloating, abdominal pain, constipation, diarrhea or delayed gastric emptying are common features in functional bowel diseases affecting, in particular, a large number of diabetic patients [1
]. The pathogenesis of GI symptoms in diabetes is not fully understood but autonomic neuropathy and abnormal glucose levels are suggested to be important. In diabetic rats neurodegeneration [2
] and apoptosis [3
] occur in myenteric neurons. Oxidative stress is considered the most important factor in causing diabetes-induced enteric neuropathy [4
]. Collectively these studies indicate the occurrence of diabetes-related neurodegenerative processes in the ENS that eventually lead to neuropathy, intestinal dysfunction and GI discomfort.
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. A number of observations also indicate that GLP1 is neuroprotective in the central nervous system [8
] and clinical trials on patients with Parkinsons disease are announced [9
]. In the peripheral nervous system GLP1 prevents experimentally induced sensory neuropathy [10
]. 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
The incretin GLP1 is encoded within the proglucagon precursor and released, together with glucagon-like peptide 2 (GLP2) in a 1:1 ratio, from L-cells in the ileum and colon in response to food ingestion. GLP2 acts as an intestinotrophic factor mainly by stimulating crypt cell proliferation but it also possesses anti-apoptotic effects and enhances nutrient absorption. Protective effects of GLP2 have been explored in clinical entities like short bowel syndrome, total parenteral nutrition-induced intestinal atrophy and in inflammatory bowel disease (IBD) [for a review see [13
]]. In trinitrobenzene sulfonic acid or dextran sodium sulfate models of IBD GLP2 treatment reduces the intestinal inflammation and counteracts inflammation-induced loss of enteric neurons. In addition, GLP2 treatment increases the number of vasoactive intestinal peptide (VIP)-expressing enteric neurons and the possibility that GLP2 effects are mediated via release of VIP is suggested [14
]. VIP exhibits established neuroprotective properties in peripheral, including enteric, and central neurons [16
Aims of the present study were to investigate possible neuroprotective effects of GLP1, GLP2 and VIP on myenteric neurons from adult rat small intestine. Two different in vitro models were used. First the ability of the three peptides to enhance neuronal survival was tested on myenteric neurons in primary culture. Next neuroprotective effects of the peptides were tested in an in vitro system in which enhanced neuronal cell death was generated by co-culturing myenteric neurons with mast cells. Receptor selectivity was, in both these models, tested by using a GLP1 receptor antagonist (exendin(9-39)amide) and a VIP receptor antagonist (hybrid neurotensin 6-11 and VIP 7-28; hybVIP).
GLP1, GLP2 and VIP were in the present study found to efficiently protect myenteric neurons in two different culture systems. Separate receptors, suggested to be neuronally expressed, were activated. These results strongly point towards a powerful therapeutic promise for these three peptides in the prevention of enteric neuropathy in diseases like diabetes, but also in inflammatory and neurodegenerative diseases.