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Submucosal arterioles in the small intestine are the main point of control for gastrointestinal (GI) circulation as they are the final resistance vessels feeding the highly perfused mucosal layer. Ischemia can lead to pathophysiology of a variety of GI tissues. In chronic intestinal inflammation, alterations in blood flow have been purported to be involved in disease etiology. The aim of this study was to characterize purinergic neurotransmitter pathways involved in physiological submucosal arteriole diameter control by the enteric nervous system long vasodilatory reflex (LVD) and to establish a protocol to determine how inflammatory neural changes affect vasodilation in the small intestine. Following euthanasia, segments of small intestine were harvested from adult male guinea pigs and changes in nerve stimulated small intestine submucosal arteriole diameter were identified using videomicroscopy techniques; vessels were preconstricted and nicotinic cholinergic transmission was blocked with hexamethonium. Purinergic receptor antagonists were applied. Immunohistochemical analysis was conducted to identify P2Y1 receptors localization. In a subset of experiments sensory neuronal excitability was initiated using phorbol dibutyrate (PDBu) shown previously to induce hyperexcitability in the sensory neurons similar to changes found in intestinal inflammation. In these experiments, intestinal segments were placed into a novel dual chamber bath separated into two portions and PDBu was applied unilaterally. Blood vessel vasodilation was either abolished or decreased by both suramin (100 μM, n=6), a non-specific P2 purinergic antagonist. MRS 2179 (10 μM, n=5), a P2Y1 specific antagonist, also decreased vasodilation, which suggests that there is a purinergic neurotransmission component to the LVD mediated by P2 receptors, including the P2Y1 subtype. Immunohistochemistry identified P2Y1 receptor staining that was uniformly punctated in both the myenteric and submucosal plexuses but specific neuronal locations of the receptor could not be identified. Nerve stimulated vasodilation was not altered by application of PDBu suggesting that neuronal hypersensitivity did not modify vessel dilation. Taken together these data suggest that purinergic receptor pathways contribute to the LVD reflex under normal conditions however more experiments are still required to fully elucidate how these pathways are affected /altered by intestinal inflammation. / Thesis (Master, Physiology) -- Queen's University, 2012-05-30 11:38:43.324

This thesis describes the study of the neurochemistry of Huntington's disease using a large series of post mortem brain tissue taken from patients with Huntington's disease and from matching controls with no previous history of neuropsychiatric disorder. There were two main aims: firstly, to identify and characterise any altered parameters of neurotransmitter systems, especially in relation to the symptomatology of the disease; secondly, to understand the role of neurotoxins in the aetiology of the disease, particularly endogenous compounds that may have derived from aberrant metabolism. Concentrations of the amino acid transmitters, GABA and glutamate, were generally significantly decreased throughout the brain in Huntington's disease, including cortical and limbic regions. Cortical deficits were not associated with the dementia of the disease, whereas caudate levels of GABA and glutamate showed a relationship with the dementia. In patients with severe chorea, the medial pallidum was found to have a relatively smaller GABA deficit than mildly choreic patients. Another novel finding was that 5HT and 5HIAA concentrations were significantly increased in most regions of the brain in Huntington's disease, perhaps reflecting abnormal tryptophan metabolism. Such changes in the cortex provide evidence for a cortical involvement in the disease. Dopamine metabolism appeared to be reduced in Huntington's disease, reflected by the significantly decreased concentrations of its major metabolite, homovanillic acid, in most regions except for the cortex (where it was increased). Neuroactive compounds of the kynurenine pathway of tryptophan metabolism were measured in Huntington's disease. Quinolinic acid concentrations were not significantly altered, however 3- hydroxykynurenine concentrations were significantly increased in the striatum and cortex. This provides the first evidence for increased concentrations of an endogenous neurotoxic compound in the brain in Huntington's disease.

Background: Recent studies have shown that the two major forms of multiple sclerosis are different in the degree of demyelination and atrophy, degree of inflammation, and extent of axonal loss. However, the majority of the previous studies that compared primary progressive and secondary progressive multiple sclerosis were carried out at the brain level. Material and methods: Human post-mortem spinal cords were used to compare the two progressive subtypes. In this project, the 5 major pathological changes associated with MS were studied in the spinal cords of primary progressive and secondary progressive multiple sclerosis. These changes include degree of demyelination, atrophy of the tissue, oligodendrocytes pathology, axonal loss, and neuronal pathology. Results: There was significant atrophy in the spinal cords of MS compared to healthy controls, which affects mainly the upper cord levels. There is a greater degree of demyelination and atrophy affecting secondary progressive compared to primary progressive especially in the upper cord levels. Oligodendrocytes numbers are dramatically reduced in the chronic lesions of WM and GM lesions. But there was high numbers of oligodendrocytes in the normally appearing GM of secondary progressive multiple sclerosis. There was greater reduction in axonal density in the secondary progressive sample especially in the normally appearing WM. Neurons were reduced in the demyelinated grey matter regions with no difference between the two disease forms in this respect. Conclusions: SPMS seem to have greater degree of tissue destruction in the form of demyelination, atrophy, and axonal loss in the normally appearing WM. However, SPMS showed greater numbers of oligodendrocytes in the demyelinated areas of the WM and the GM. Although the disability scale in the two examined groups was found to be similar, the tissue damage appeared to be variable.

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