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1.
Neurogastroenterol Motil ; 20(4): 418-29, 2008 Apr.
Article in English | MEDLINE | ID: mdl-18371012

ABSTRACT

The objective of this article is to review the clinical presentation and neurobiology of degeneration of the enteric nervous system with emphasis on human data where available. Constipation, incontinence and evacuation disorders are frequently encountered in the ageing population. Healthy lower gastrointestinal function is essential for successful ageing as it is critical to maintaining independence and autonomy to pursue further activity. One clinical expression of enteric neurodegeneration is constipation. However, the aetiology may be multifactorial as disturbances of epithelial, muscle or neural function may all result from neurodegeneration. There is evidence of loss of excitatory (e.g. cholinergic) enteric neurons and interstitial cells of Cajal, whereas inhibitory (including nitrergic) neurons appear unaffected. Understanding neurodegeneration in the enteric nervous system is key to developing treatments to reverse it. Neurotrophins have been shown to accelerate colonic transit and relieve constipation in the medium term; they are also implicated in maintenance programmes in adult enteric neurons through a role in antioxidant defence. However, their effects in ageing colon require further study. There is evidence that 5-HT(2) and 5-HT(4) mechanisms are involved in development, maintenance and survival of enteric neurons. Further research is needed to understand and potentially reverse enteric neurodegeneration.


Subject(s)
Aging/pathology , Enteric Nervous System/pathology , Intestines/innervation , Intestines/pathology , Nerve Degeneration/pathology , Aged , Aged, 80 and over , Aging/physiology , Animals , Constipation/pathology , Constipation/physiopathology , Enteric Nervous System/physiopathology , Female , Humans , Male
2.
Neurogastroenterol Motil ; 20(3): 185-96, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18257768

ABSTRACT

The objective of this article is to review the clinical presentation and neurobiology of degeneration of the enteric nervous system with emphasis on human data where available. Constipation, incontinence and evacuation disorders are frequently encountered in the ageing population. Healthy lower gastrointestinal function is essential for successful ageing as it is critical to maintaining independence and autonomy to pursue further activity. One clinical expression of enteric neurodegeneration is constipation. However, the aetiology may be multifactorial as disturbances of epithelial, muscle or neural function may all result from neurodegeneration. There is evidence of loss of excitatory (e.g. cholinergic) enteric neurons and interstitial cells of Cajal, whereas inhibitory (including nitrergic) neurons appear unaffected. Understanding neurodegeneration in the enteric nervous system is key to developing treatments to reverse it. Neurotrophins have been shown to accelerate colonic transit and relieve constipation in the medium term; they are also implicated in maintenance programmes in adult enteric neurons through a role in antioxidant defence. However, their effects in ageing colon require further study. There is evidence that 5-HT(2) and 5-HT(4) mechanisms are involved in development, maintenance and survival of enteric neurons. Further research is needed to understand and potentially reverse enteric neurodegeneration.


Subject(s)
Aging/physiology , Enteric Nervous System/physiopathology , Neurodegenerative Diseases/physiopathology , Aged/physiology , Animals , Enteric Nervous System/pathology , Humans , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/epidemiology , Neurodegenerative Diseases/pathology , Neuromuscular Diseases/drug therapy , Neuromuscular Diseases/pathology , Neuromuscular Diseases/physiopathology , Neurons/pathology , Risk Factors , Serotonin/physiology
3.
Auton Neurosci ; 89(1-2): 125-7, 2001 Jun 20.
Article in English | MEDLINE | ID: mdl-11474640

ABSTRACT

Pressures generated by the pharyngeal constrictor muscles and proximal esophagus involve acetylcholine-induced muscle contractions. We hypothesized that the pharyngo-esophageal pressure gradient is related to choline acetyltransferase activity. In nine anesthetized cats, hypopharyngeal pressure and proximal esophageal pressure were recorded with a solid state transducer assembly. Enzymatic activities in the thyropharyngeus, cricopharyngeus, and proximal esophageal muscles were measured. Hypopharyngeal pressure was higher than the proximal esophagus (p < 0.01), and choline acetyltransferase activity was higher in the cricopharyngeus compared to the proximal esophagus ( p < 0.05). The pressure gradient between the hypopharynx and proximal esophagus may be influenced by the activity of choline acetyltransferase.


Subject(s)
Choline O-Acetyltransferase/metabolism , Esophagus/innervation , Pharynx/innervation , Vagus Nerve/enzymology , Acetylcholinesterase/metabolism , Animals , Cats , Deglutition/physiology , Esophagus/physiology , Pharynx/physiology , Pressure , Vagus Nerve/physiology
6.
Dig Dis Sci ; 45(9): 1814-9, 2000 Sep.
Article in English | MEDLINE | ID: mdl-11052325

ABSTRACT

It has been proposed that oxidative stress is involved in the pathophysiology of ulcerative colitis. We have reported the depletion of the nonenzymatic antioxidant, glutathione, in colon from active and inactive ulcerative colitis. The colon contains several biochemically linked antioxidant systems. We hypothesized that diminished total antioxidant capacity in active ulcerative colitis would be associated with increased colonic lipid peroxidation. This study was designed to determine total antioxidant capacity and lipid hydroperoxide levels using colon obtained at surgery from controls (N = 16; 4 females, 12 males; mean age 70 years), and active and inactive ulcerative colitis (N = 15; 3 females, 12 males; mean age 39). Total antioxidant capacity of control colon was higher in muscularis externa compared to the mucosal-submucosal layer (P < 0.05). There were no differences in colonic total antioxidant capacity or lipid hydroperoxide levels comparing control colon to inactive and active ulcerative colitis. The results did not support depletion of tissue total antioxidant capacity by free radicals. Depletion of glutathione in ulcerative colitis may be a specific disorder rather than a secondary defect attributable to global oxidative stress. Nonspecific antioxidant supplements appear unlikely to be beneficial in the treatment of ulcerative colitis.


Subject(s)
Antioxidants/metabolism , Colitis, Ulcerative/metabolism , Colon/metabolism , Adult , Aged , Chronic Disease , Female , Humans , In Vitro Techniques , Intestinal Mucosa/metabolism , Lipid Peroxides/metabolism , Male
9.
Dis Colon Rectum ; 43(6): 821-8, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10859084

ABSTRACT

PURPOSE: Nitric oxide modulates human colonic smooth muscle function. To determine whether nitric oxide production is altered in colon from acquired megacolon, we measured cholinergic nerve-mediated contractions in vitro before and after inhibition of nitric oxide synthase. METHODS: Intramural nerves in circular smooth muscle from histologically normal colon (n = 12) and acquired megacolon (n = 3) were activated by electrical field stimulation. RESULTS: In controls blockade of nitric oxide synthase by N(G)-Nitro-L-Arginine induced increases (P < 0.05) in amplitude of contractions; these increases in amplitudes were blocked by L-Arginine (analysis of variance; P < 0.05). By contrast, blockade of nitric oxide synthase did not increase amplitudes of contractions with circular smooth muscle from acquired megacolon. An immediate phasic contraction was blocked by atropine sulfate. CONCLUSIONS: The results support the concept that nitric oxide production modulates cholinergic nerve-mediated contractions in normal colonic circular muscle, whereas acquired megacolon is associated with altered release of this inhibitory neurochemical. Potential explanations include depletion of tissue L-Arginine, decreased capacity to recycle citrulline to arginine, or decreased release of vasoactive intestinal peptide from circular smooth muscle in acquired megacolon.


Subject(s)
Colon/metabolism , Megacolon/metabolism , Muscle, Smooth/metabolism , Nitric Oxide/biosynthesis , Aged , Aged, 80 and over , Electric Stimulation , Female , Humans , Male , Middle Aged , Nitric Oxide Synthase/antagonists & inhibitors
10.
Dig Dis Sci ; 45(11): 2115-21, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11215724

ABSTRACT

Glutathione is a nonenzymatic antioxidant synthesized by most animal cells and is depleted in inflammatory bowel disease. The effects of glutathione depletion on intestinal histology and inhibitory neurochemicals was examined in a mouse model. Glutathione depletion in A/J mice involved inhibition of gamma-glutamylcysteine synthetase using L-buthionine-(S,R)-sulfoximine (BSO) for 10 days. Ileum and colon were obtained from saline-control mice, BSO-treated mice, and BSO-treated mice receiving ascorbate or glutathione monoethylester. Glutathione, lipid peroxides, and nicotineamide adenine dinucleotide phosphate diaphorase activity were measured by colorimetric assays. Vasoactive intestinal peptide was measured by radioimmunoassay. Glutathione depletion induced enlargement of mucosal-submucosal lymphoid aggregates without germinal centers in ileum and colon. These aggregates were prevented by supplementation with glutathione monoethylester but not ascorbate. Tissue levels of inhibitory neurochemicals were unchanged. Depletion of glutathione appears to induce enlarged lymphoid aggregates by recruitment of lymphocytes from the peripheral circulation. A component of the inflammation that develops in inflammatory bowel disease could be related to depletion of tissue levels of glutathione.


Subject(s)
Glutathione/physiology , Lymphoid Tissue/pathology , Oxidative Stress/physiology , Animals , Disease Models, Animal , Hypertrophy , Inflammatory Bowel Diseases/pathology , Mice , Mice, Inbred A
11.
Percept Mot Skills ; 89(2): 607-25, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10597597

ABSTRACT

Clinical and epidemiological studies have supported the belief that human beings exposed to stressful life events are vulnerable to the symptomatology consistent with posttraumatic stress disorder (PTSD). However, early detection of symptoms consistent with PTSD oftentimes does not occur within the medicolegal arena. The importance of an early and accurate diagnosis is emphasized. Fortunately, the diagnosis of PTSD has become more clearly conceptualized in the DSM-IV criteria. Many of the characteristics consistent with this diagnosis are measured through the use of relatively recently developed and refined psychometric measures including the Posttraumatic Stress Diagnostic Scale, the Trauma Symptom Inventory, and the Personality Assessment Inventory-2. Additional measures including the Computerized Response Bias Test, the Word Memory Test, and the Validity Indicator Profile can detect exaggeration of symptoms without using specific tests for symptom validity. These measures, as well as biochemical determinations, are reviewed and presented along with the over-all structured clinical interviews and mental status examinations of two patients for a better understanding of the multimethod approach which establishes the reliability of the PTSD diagnosis.


Subject(s)
Stress Disorders, Post-Traumatic/diagnosis , Adult , Clinical Protocols , Cognitive Behavioral Therapy , Diagnosis, Differential , Female , Humans , Life Change Events , MMPI/statistics & numerical data , Male , Malingering/diagnosis , Malingering/psychology , Middle Aged , Personality Assessment/statistics & numerical data , Personality Inventory/statistics & numerical data , Psychiatric Status Rating Scales/statistics & numerical data , Psychometrics , Psychotropic Drugs/therapeutic use , Rehabilitation, Vocational , Reproducibility of Results , Severity of Illness Index , Stress Disorders, Post-Traumatic/psychology , Stress Disorders, Post-Traumatic/therapy
14.
Neurosci Lett ; 266(2): 97-100, 1999 May 07.
Article in English | MEDLINE | ID: mdl-10353336

ABSTRACT

Transplantation of the small intestine is a neural model that could include extrinsic denervation, loss of intrinsic enteric neurons, or loss of intrinsic neural pathways. Nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity was measured in normal rat ileum, ileum 3 months after resection of the jejunum, and ileum 3 months after isotransplantation of the ileum. The distribution of NADPH diaphorase activity and immunoreactive neuronal nitric oxide synthase were examined. Nicotinamide adenine dinucleotide phosphate diaphorase activity was increased in transplanted ileum (16.5+/-3.5 mU/mg protein) compared to normal controls (6.6+/-0.7) and resection controls (6.8+/-0.6) (P < 0.05, ANOVA). Histologically, NADPH diaphorase activity and immunoreactive nitric oxide synthase appeared increased within nerve cell bodies following transplantation. These findings may represent an adaptive response of the enteric nervous system to extrinsic denervation. Loss of intrinsic neural pathways was not supported as a mechanism.


Subject(s)
Intestine, Small/transplantation , Nitric Oxide Synthase/biosynthesis , Analysis of Variance , Animals , Intestine, Small/metabolism , NADPH Dehydrogenase/metabolism , Rats , Rats, Inbred Lew
19.
J Surg Res ; 80(2): 320-5, 1998 Dec.
Article in English | MEDLINE | ID: mdl-9878332

ABSTRACT

Despite its great promise, small intestinal transplantation in some patients is complicated by difficult postoperative management. The reasons for this are complex. In a rat model of small intestinal transplantation, frequencies of migrating myoelectric complexes during fasting are reduced in ileal isografts and muscarinic receptor density is decreased. We hypothesized that the distribution of muscarinic 1 receptors localized to enteric neurons is altered after small intestinal transplantation. Distal small intestine was orthotopically transplanted in Lewis-to-Lewis donor-recipient combinations. At 3 months, transplanted and normal ileum was obtained to prepare membrane fractions. [N-methyl-3H]Scopolamine served as ligand, while scopolamine methylbromide, pirenzepine, and methoctramine were used in competitive homologous and heterologous displacement experiments. Receptor subtype models were examined by nonlinear regression analysis. In normal and transplanted ileum, heterologous displacement was consistent with three site models (P < 0.05). In normals, the muscarinic 1 receptor subtype was most abundant, with a relative distribution of 69 to 78%. There was a relative distribution of 13 to 16% for muscarinic 3 receptor subtype. After transplantation, the muscarinic 1 subtype decreased to a mean of 45% but the muscarinic 3 subtype increased to a mean of 42%. Using pirenzepine, mean pKD values were not different between the two groups. It is concluded that the decrease in muscarinic 1 receptor subtype after transplantation could be related to neuronal cell loss or to downregulation of the expression of muscarinic 1 receptors. The results did not support defective posttranslational processing of receptor proteins.


Subject(s)
Intestine, Small/metabolism , Intestine, Small/transplantation , Receptors, Muscarinic/classification , Receptors, Muscarinic/metabolism , Animals , Binding, Competitive , Diamines/metabolism , Gastrointestinal Motility/physiology , Intestine, Small/innervation , Kinetics , Muscarinic Antagonists/metabolism , Muscle, Smooth/innervation , Muscle, Smooth/metabolism , Pirenzepine/metabolism , Protein Processing, Post-Translational , Radioligand Assay , Rats , Rats, Inbred Lew , Receptor, Muscarinic M1 , Receptor, Muscarinic M2 , Receptor, Muscarinic M3 , Tissue Distribution , Transplantation, Isogeneic
20.
Neurosci Lett ; 235(1-2): 77-80, 1997 Oct 10.
Article in English | MEDLINE | ID: mdl-9389600

ABSTRACT

Antioxidants may delay or prevent neural diseases. Depletion of the non-enzymatic antioxidant, glutathione, in a mouse model was produced by inhibiting its rate-limiting enzyme, gamma-glutamylcysteine synthetase, for 7 weeks. Ileum and colon were obtained from treated and control (saline) mice. Glutathione levels and nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity were determined by spectrophotometric assays; vasoactive intestinal peptide (VIP) levels were measured by radioimmunoassay. Glutathione levels were higher in ileum than colon. Colonic glutathione was decreased in treated mice compared to controls; there were no differences in ileal glutathione levels. VIP was decreased in ileum compared to controls, while NADPH diaphorase activity was decreased in colon compared to controls. In this chronic mouse model, glutathione appeared to regulate expression of enteric inhibitory nerve cell products.


Subject(s)
Enteric Nervous System/metabolism , Glutathione/metabolism , NADPH Dehydrogenase/metabolism , Vasoactive Intestinal Peptide/metabolism , Animals , Buthionine Sulfoximine/pharmacology , Colon/metabolism , Enzyme Inhibitors/pharmacology , Glutamate-Cysteine Ligase/antagonists & inhibitors , Ileum/metabolism , Mice , Mice, Inbred Strains , Radioimmunoassay
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