Acetylcholine in Diabetic Enteric Nervous System

Midwestern University, Downers Grove IL

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Abstract

DESCRIPTION (provided by applicant): Diabetics report a greater frequency of constipation, diarrhea, urgency, and fecal incontinence than the general population that may reflect alterations in gastrointestinal (GI) motility due to neuropathy of autonomic nerves. GI motility is controlled by extrinsic autonomic nerves (sympathetic and parasympathetic) that project to the GI tract and intrinsic autonomic nerves (enteric nerves) located in the wall of the gut. Degenerating neurons may release different amounts and/or proportions of classical and peptide neurotransmitters, synthesize novel proteins, synthesize another splice variant of the same protein, or degrade proteins more quickly to protect them from or to promote apoptosis. The contribution of enteric neuropathy to GI complications will be determined using ileum from streptozotocin-induced diabetic guinea pigs (6 weeks after treatment). Alterations in motility and synaptic transmission will be correlated with alterations in neurotransmitter release, enzyme content, and extent of dendritic branching. Cholinergic contractions will be assessed using a tissue bath setup. Abnormal motility will be corrected pharmacologically using serotonin4 agonists, alpha-adrenergic antagonists and/or antagonists of nitric oxide synthase. Acetylcholine release will be assessed by HPLC with electrochemical detection. Dendritic branching of cholinergic neurons will be assessed using immunohistochemistry of choline acetyltransferase (CHAT) and bitmap analysis of tertiary fiber tracts. Cholinergic and purinergic fast excitatory postsynaptic potentials will be recorded from myenteric neurons. Adaptations of enteric neurons to destruction of their own processes or to diminished innervation by extrinsic nerves caused by diabetes will provide understanding in the plasticity of enteric nerves to adapt during disease conditions. Once these adaptations are understood, GI complications experienced by diabetic patients can be more effectively treated.