Anatomy and Neuroscience - Research Publications
Permanent URI for this collection
Search Results
1 - 7 of 7
-
ItemSqualamine Restores the Function of the Enteric Nervous System in Mouse Models of Parkinson's Disease(IOS Press, 2020-10-27)Background: Parkinson’s disease (PD) is a progressive neurodegenerative disorder thought to be caused by accumulation of α-synuclein (α-syn) within the brain, autonomic nerves, and the enteric nervous system (ENS). Involvement of the ENS in PD often precedes the onset of the classic motor signs of PD by many years at a time when severe constipation represents a major morbidity. Studies conducted in vitro and in vivo, have shown that squalamine, a zwitterionic amphipathic aminosterol, originally isolated from the liver of the dogfish shark, effectively displaces membrane-bound α-syn. Objective: Here we explore the electrophysiological effect of squalamine on the gastrointestinal (GI) tract of mouse models of PD engineered to express the highly aggregating A53T human α-syn mutant. Methods: GI motility and in vivo response to oral squalamine in PD model mice and controls were assessed using an in vitro tissue motility protocol and via fecal pellet output. Vagal afferent response to squalamine was measured using extracellular mesenteric nerve recordings from the jejunum. Whole cell patch clamp was performed to measure response to squalamine in the myenteric plexus. Results: Squalamine effectively restores disordered colonic motility in vivo and within minutes of local application to the bowel. We show that topical squalamine exposure to intrinsic primary afferent neurons (IPANs) of the ENS rapidly restores excitability. Conclusion: These observations may help to explain how squalamine may promote gut propulsive activity through local effects on IPANs in the ENS, and further support its possible utility in the treatment of constipation in patients with PD.
-
ItemATH434 Reverses Colorectal Dysfunction in the A53T Mouse Model of Parkinson's Disease(IOS PRESS, 2021)BACKGROUND: Gastrointestinal (GI) complications, that severely impact patient quality of life, are a common occurrence in patients with Parkinson's disease (PD). Damage to enteric neurons and the accumulation of alpha-synuclein in the enteric nervous system (ENS) are thought to contribute to this phenotype. Copper or iron chelators, that bind excess or labile metal ions, can prevent aggregation of alpha-synuclein in the brain and alleviate motor-symptoms in preclinical models of PD. OBJECTIVE: We investigated the effect of ATH434 (formally PBT434), a small molecule, orally bioavailable, moderate-affinity iron chelator, on colonic propulsion and whole gut transit in A53T alpha-synuclein transgenic mice. METHODS: Mice were fed ATH434 (30 mg/kg/day) for either 4 months (beginning at ∼15 months of age), after the onset of slowed propulsion ("treatment group"), or for 3 months (beginning at ∼12 months of age), prior to slowed propulsion ("prevention group"). RESULTS: ATH434, given after dysfunction was established, resulted in a reversal of slowed colonic propulsion and gut transit deficits in A53T mice to WT levels. In addition, ATH434 administered from 12 months prevented the slowed bead expulsion at 15 months but did not alter deficits in gut transit time when compared to vehicle-treated A53T mice. The proportion of neurons with nuclear Hu+ translocation, an indicator of neuronal stress in the ENS, was significantly greater in A53T than WT mice, and was reduced in both groups when ATH434 was administered. CONCLUSION: ATH434 can reverse some of the GI deficits and enteric neuropathy that occur in a mouse model of PD, and thus may have potential clinical benefit in alleviating the GI dysfunctions associated with PD.
-
ItemChronic isolation stress is associated with increased colonic and motor symptoms in the A53T mouse model of Parkinson's disease(WILEY, 2020-03)BACKGROUND: Chronic stress exacerbates motor deficits and increases dopaminergic cell loss in several rodent models of Parkinson's disease (PD). However, little is known about effects of stress on gastrointestinal (GI) dysfunction, a common non-motor symptom of PD. We aimed to determine whether chronic stress exacerbates GI dysfunction in the A53T mouse model of PD and whether this relates to changes in α-synuclein distribution. METHODS: Chronic isolation stress was induced by single-housing WT and homozygote A53T mice between 5 and 15 months of age. GI and motor function were compared with mice that had been group-housed. KEY RESULTS: Chronic isolation stress increased plasma corticosterone and exacerbated deficits in colonic propulsion and whole-gut transit in A53T mice and also increased motor deficits. However, our results indicated that the novel environment-induced defecation response, a common method used to evaluate colorectal function, was not a useful test to measure exacerbation of GI dysfunction, most likely because of the reported reduced level of anxiety in A53T mice. A53T mice had lower corticosterone levels than WT mice under both housing conditions, but single-housing increased levels for both genotypes. Enteric neuropathy was observed in aging A53T mice and A53T mice had a greater accumulation of alpha-synuclein (αsyn) in myenteric ganglia under both housing conditions. CONCLUSIONS & INFERENCES: Chronic isolation stress exacerbates PD-associated GI dysfunction, in addition to increasing motor deficits. However, these changes in GI symptoms are not directly related to corticosterone levels, worsened enteric neuropathy, or enteric αsyn accumulation.
-
ItemInvestigation of nerve pathways mediating colorectal dysfunction in Parkinson's disease model produced by lesion of nigrostriatal dopaminergic neurons(WILEY, 2020-09)BACKGROUND: Gastrointestinal (GI) dysfunction, including constipation, is a common non-motor symptom of Parkinson's disease (PD). The toxin 6-hydroxydopamine (6OHDA) produces the symptoms of PD, surprisingly including constipation, after it is injected into the medial forebrain bundle (MFB). However, the mechanisms involved in PD-associated constipation caused by central application of 6OHDA remain unknown. We investigated effects of 6OHDA lesioning of the MFB on motor performance and GI function. METHODS: Male Sprague Dawley rats were unilaterally injected with 6OHDA in the MFB. Colorectal propulsion was assessed by bead expulsion after 4 weeks and by recording colorectal contractions and propulsion after 5 weeks. Enteric nervous system (ENS) neuropathy was examined by immunohistochemistry. KEY RESULTS: When compared to shams, 6OHDA-lesioned rats had significantly increased times of bead expulsion from the colorectum, indicative of colon dysmotility. Administration of the colokinetic, capromorelin, that stimulates defecation centers in the spinal cord, increased the number of contractions and colorectal propulsion in both groups compared to baseline; however, the effectiveness of capromorelin in 6OHDA-lesioned rats was significantly reduced in comparison with shams, indicating that 6OHDA animals have reduced responsiveness of the spinal defecation centers. Enteric neuropathy was observed in the distal colon, revealing that lesion of the MFB has downstream effects at the cellular level, remote from the site of 6OHDA administration. CONCLUSIONS & INFERENCES: We conclude that there are trans-synaptic effects of the proximal, forebrain, lesion of pathways from the brain that send signals down the spinal cord, at the levels of the defecation centers and the ENS.
-
ItemNo Preview AvailableQuantitation and chemical coding of enteroendocrine cell populations in the human jejunum(SPRINGER, 2020-01)Recent studies reveal substantial species and regional differences in enteroendocrine cell (EEC) populations, including differences in patterns of hormone coexpression, which limit extrapolation between animal models and human. In this study, jejunal samples, with no histologically identifiable pathology, from patients undergoing Whipple's procedure were investigated for the presence of gastrointestinal hormones using double- and triple-labelling immunohistochemistry and high-resolution confocal microscopy. Ten hormones (5-HT, CCK, secretin, proglucagon-derived peptides, PYY, GIP, somatostatin, neurotensin, ghrelin and motilin) were localised in EEC of the human jejunum. If only single staining is considered, the most numerous EEC were those containing 5-HT, CCK, ghrelin, GIP, motilin, secretin and proglucagon-derived peptides. All hormones had some degree of colocalisation with other hormones. This included a population of EEC in which GIP, CCK and proglucagon-derived peptides are costored, and four 5-HT cell populations, 5-HT/GIP, 5-HT/ghrelin, 5-HT/PYY, and 5-HT/secretin cell groups, and a high degree of overlap between motilin and ghrelin. The presence of 5-HT in many secretin cells is consistent across species, whereas lack of 5-HT and CCK colocalisation distinguishes human from mouse. It seems likely that the different subclasses of 5-HT cells subserve different roles. At a subcellular level, we examined the vesicular localisation of secretin and 5-HT, and found these to be separately stored. We conclude that hormone-containing cells in the human jejunum do not comply with a one-cell, one-hormone classification and that colocalisations of hormones are likely to define subtypes of EEC that have different roles.
-
ItemBetaine and Isoquinoline Alkaloids Protect against Heat Stress and Colonic Permeability in Growing Pigs(MDPI, 2020-10)Heat stress (HS) compromises productivity of pork production, in part as a result of increased oxidative stress and inflammatory responses, particularly within the gastrointestinal tract. This study aimed to investigate whether plant-derived betaine and isoquinoline alkaloids could ameliorate HS in pigs. Fifty female Large White × Landrace grower pigs, which were acclimated to control (CON), control plus betaine (BET), or control plus isoquinoline alkaloids (IQA) diets for 14 days were then exposed to heat stress or thermoneutral condition. Both BET and IQA partially ameliorated increases in respiration rate (p = 0.013) and rectal temperature (p = 0.001) associated with HS conditions. Heat stress increased salivary cortisol concentrations and reduced plasma creatinine, lactate, and thyroid hormone concentrations. Heat stress increased colon FD4 permeability, which was reduced by IQA (p = 0.030). Heat stress increased inflammation in the jejunum and ileum, as indicated by elevated interleukin-1β (p = 0.022) in the jejunum and interleukin-1β (p = 0.004) and interleukin-8 (p = 0.001) in the ileum. No differences in plasma total antioxidant capacity (TAC) were observed with HS, but betaine increased plasma TAC compared to IQA. Dietary BET increased betaine concentrations in the jejunum, ileum (p < 0.001 for both), plasma, liver, kidney (p < 0.010 for all), urine (p = 0.002) and tended to be higher in muscle (p = 0.084). Betaine concentration was not influenced by HS, but it tended to be higher in plasma and accumulated in the liver. These data suggest that betaine and isoquinoline alkaloids supplementation ameliorated consequences of heat stress in grower pigs and protected against HS induced increases in colonic permeability.
-
ItemDietary Betaine Improves Intestinal Barrier Function and Ameliorates the Impact of Heat Stress in Multiple Vital Organs as Measured by Evans Blue Dye in Broiler Chickens(MDPI, 2020-01)In a 2 × 2 factorial design, 60 male Ross-308 broilers were fed either a control or 1 g/kg betaine diet and housed under thermoneutral (TN) or heat stress (HS) conditions. Broilers were acclimated to diets for 1 week under TN (25 °C), then either kept at TN or HS, where the temperature increased 8 h/day at 33 °C and 16 h/day at 25 °C for up to 10 days. Respiration rate (RR) was measured at four time points, and on each of 1, 2, 3, 7 and 10 days of HS, 12 broilers were injected with 0.5 mg/kg of Evans Blue Dye (EBD) solution to quantify regional changes in tissue damage. Betaine was quantified in tissues, and ileal damage was assessed via morphometry and transepithelial resistance (TER). Heat stress elevated RR (p < 0.001) and resulted in reduced villous height (p = 0.009) and TER (p < 0.001), while dietary betaine lowered RR during HS (p < 0.001), increased betaine distribution into tissues, and improved ileal villous height (p < 0.001) and TER (p = 0.006). Heat stress increased EBD in the muscle and kidney of chickens fed the control diet but not in those receiving betaine. Overall, these data indicate that supplemented betaine is distributed to vital organs and the gastrointestinal tract, where it is associated with improved tolerance of HS. Furthermore, EBD markers help reveal the effects of HS on organs dysfunction.