Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 5 uppsatser.

Orientador: Wilma Aparecida Starke Buzetti / Banca: Solange Maria Gennari / Banca: Maria de Lurdes de Azevedo Rodrigues / Banca: Rosangela Zacarias Machado / Banca: Gervasio Henrique Bechara / Resumo: Para estudar a cinética populacional de células imune/inflamatórias na infecção natural por Toxocara vitulorum em bezerros búfalos, realizou-se a quantificação de mastócitos, eosinófilos, linfócitos intraepiteliais (LIE) e células caliciformes na camada intraepitelial e de macrófagos na parede do intestino delgado. Para isto, amostras de tecidos foram retiradas do duodeno, jejuno e íleo de seis grupos de animais, de acordo com o resultado do exame coprológico, ou seja: animais que estavam no início ou ascensão (1), no pico (2) do parasitismo, durante as fases de declínio ou expulsão (3), e de pós-expulsão dos parasitas (4), além de dois grupos controles de animais não parasitados por T. vitulorum com idades médias entre 30 (C30) e 50 (C50) dias. Pelo estudo morfológico, feito através de mensurações de todas as camadas da parede do intestino delgado, constatou-se somente uma significativa atrofia vilosa no duodeno, durante as fases de ascensão, de pico e de expulsão do parasita, mas a hipertrofia muscular não foi observada. Concluiu-se que a infecção pelo nematódeo T. vitulorum em bezerros búfalos foi responsável pela hiperplasia celular (LIEs, células caliciformes, eosinófilos e mastócitos) na camada intraepitelial e pela interação entre mastócitos e processos nervosos na mucosa, nos plexos submucoso e mioentérico. Como estas alterações celulares predomindando no pico da infecção normalizaram-se após a expulsão, concluiu-se também que elastiveram participação no mecanismo imunológico celular de controle e expulsão do parasita pelo hospedeiro. O macrófago presente em maior quantidade na fase da pós-expulsão sugeriu uma importante participação destas células na recuperação das lesões inflamatórias nesta infecção. / Abstract: The populational kinetics of immune/inflammatory cells was studied in the wall of the small intestine from buffalo calves naturally infected with Toxocara vitulorum. Samples of tissues were removed from duodenum, jejunum and ileum of four groups of animals during the beginning of the infection, at the peak of egg output, during the period of expulsion and post-expulsion of the worms, as well as from uninfected calves. Cells (mast cells, eosinophils, intraepithelial lymphocytes - IEL and goblet cells) present in the epithelial layer (intraepithelial) of the small intestine were counted. In the duodenum, jejunum and ileum, the population of mast cells, eosinophils and lymphocytes increased significantly during the peak of the infection. Goblet cell numbers increased also during the beginning and at the peak of the infection. The decline of the number of these cells occurred during the periods of expulsion of the worms reaching to uninfected control counts at the post-expulsion period indicated a role of these cells in the process of expulsion of T. vitulorum by the buffalo calves. Morphological examinations showed a significant vilar atrophy, particularly in the duodenum during the beginning, peak and during the phase of expulsion of the worms, but smooth muscle hypertrophy or other alteration was not observed in any phase of the infection. In conclusion, the infection by T. vitulorum in buffalo calves elicited cellular hyperplasy of LIEs, goblet cells, eosinophils and mast cells in the intraepithelial layer of the small intestines and association between mast cells and nervous process in the mucosa and in the submucosal and mioentérico plexa, these cellular changes might be important for the worm expulsion. The macrophages presents in high numbers in the post-expulsion phase might have important role in the recovery of the infection. / Doutor

Embora diversos trabalhos relatem as alterações fisiológicas que ocorrem no trato gastrointestinal com a senescência e com o exercício físico, poucos são os relatos morfológicos a respeito destas duas variantes. Portanto, o objetivo deste trabalho foi verificar qual a influência da atividade física (corrida em esteira) na ultraestrutura, na densidade neuronal (neurônios/mm2) e na área do perfil do corpo celular (µm2) dos neurônios mioentéricos do jejuno de ratos com a idade. Para tanto, foram utilizados 45 ratos Wistar divididos em três grupos: C (controle com seis meses), S (sedentário com 12 meses) e T (treinado com 12 meses) sendo utilizado 5 animais para cada técnica/grupo. Os preparados de membrana do jejuno foram corados com as técnicas histoquímicas de NADH e NADPH para estimar o número de neurônios e a área do perfil neuronal. Os resultados alcançados nos testes de esforço (TEMs) forçam sempre maiores no grupo T do que no grupo S. O peso dos animais do grupo T foi menor que os do grupo S. A área do jejuno-íleo foi mensurada e não presentou diferença significativa (P>0,05) entre os animais dos grupos C, S e T. Com exceção da membrana basal que apresentou-se menos definida e da região periganglionar que encontrava-se mais espassada nos animais do grupo S, não foram identificadas alterações ultraestruturais e no arranjo do plexo mioentéricos entre os grupos. A densidade dos neurônios reativos a NADH-diaforase foi menor (P<0,05) nos animais do grupo S (67,76±3,7) em relação aos animais dos grupos C (104,8±5,86) e T (95,18±7,18). Para os neurônios NADPH-diaforase, observou-se menor densidade neuronal nos grupos S (32,32±1,7) e T (27,39±1,2) comparado com o grupo C (44,53±4,5), mas diferenças significativas não foram evidencias entre os grupos S e T. A área do perfil do corpo celular (µm2) dos neurônios NADH- diaforase positivos diminuiu no grupo S (103,4±8,68) e aumento no grupo T (198,4±8,22) em relação ao grupo C (167±6,93). A área neuronal mensurada nos neurônios NADPH-diaforase positivos foi estatisticamente menor entre os grupos T (129,9±9,55) e C (186,8±9,34), mas não foram observadas diferenças entre estes grupos com o grupo S (157,3±3,64). Contudo, as alterações observadas indicam poucas são as influências do envelhecimento em animais com 12 meses de idade. / Although several works tell the physiologic alterations that they happen in the treatment gastrointestinal with the aging and with the physical exercise, few are the morphologic reports regarding these two variants. Therefore, the objective of this work was to verify which the influence of the physical activity (treadmill workout) in the ultrastructural, in the in the neuronal density (neurons/mm2) and in the profile area of the cellular body (µm2) of the myenteric neurons of the jejunum of rats with aging. For so much, 45 Wistar rats were used and they were divided in three groups: C (controls with six months), S (sedentary with 12 months) and T (trained with 12 months) being used 5 animals for each technique/group. The whole mounts of the jejunum were stained with the NADH and NADPH histochemistry techniques to estimate the density and the profile area of the myenteric neurons. The results of the maximal exercise test (METs) they always bigger in the T group than S group. The weight of the animals of the T group was smaller than S group. The jejunum-ileum area was measured and it didn\'t present significant difference (P>0.05) among the animals of the C, s and T groups. Except for the basal membrane that it came less defined and of the periganglionic area that was more scattered in the animals of the S group, they were not identified ultrastructural alterations and in the arrangement of the myenteric plexus among the groups. The density of the NADH-diaphorase neurons was smaller (P<0.05) in the animals of the S group (67.76±3.7) in relation to the animals of the C (104.8±5.86) and T (95.18±7.18) groups. For the NADPH- diaphorase neurons, smaller neuronal density was observed in the S (32.32±1.7) and T (27.39±1.2) groups compared with the C group (44.53±4.5), but the significant differentiate didn\'t evidence among the S and T groups. The profile area (µm2) of the NADH-diaphorase neurons decreased in the S group (103.4±8.68) and increase in the T group (198.4±8.22) in relation to the C group (167±6.93). The profile area of the NADPH-diaphorase neurons was smaller statically among the T (129.9±9.55) and C (186.8±9.34) groups, but differences were not observed among these groups with the S group (157.3±3.64). However, the observed alterations indicate little are the influences of the aging in animals with 12 months age.

Diarrhoea is one of the killer diseases resulting from the dehydration and loss of electrolytes through profuse and excessive excretion of loose stool. The pathoaetiologies include infections, intestinal inflammation, imbalanced intestinal oxidative homeostasis and altered motility. Treatment with oral rehydration therapy (ORT) is a key intervention especially in secretory diarrhoea as supportive therapy. Symptomatic and non-symptomatic therapies directed at treating the intestinal tissues are available. However, these conventional treatments are still not sufficient in curing diarrhoea due to their associated hazards such as the development and spread of drugresistant pathogens, changes in normal intestinal bacteria flora and potential chronic toxicity. Therapies targeted at intestinal tissue include antimotility and antisecretory agents have adverse effects such as addictiveness, constipation and fatal ischaemic colitis. Many ethnopharmacological and ethnobotanical therapies for treating diarrhoea exist among different cultures. The aims of this study were to evaluate the biological activities of plant extracts against some diarrhoeal pathophysiologies. A literature search in English of published articles and books that discussed ethnobotanical uses of medicinal plants in southern Africa was conducted. A list of 230 medicinal plants used in South African traditional medicines for treating diarrhoea and associated complications was created. The list included family, genus, species, biological activities and bioactive isolates as well as the remedies for diarrhoea. Twenty seven species were selected to evaluate for antimicrobial, antioxidant and anti-inflammatory activities. Safety of the plants was determined by determining the cytotoxicity of the crude extracts against Vero African green monkey kidney cell lines using a standard method. Motility effects of Bauhinia galpinii (BGE) and <i<Combretum vendae (CVE) were determined by modulation of the contractility process of the isolated rat ileum induced by spasmogens. Phenolic compositions of the crude extract were determined using various standard methods and finally bioactivity guided isolation of antimicrobial and antioxidant compounds from BGE and CVE were carried out using open column chromatography. Identification and characterization of the isolated compounds was achieved by NMR, El-MS and UV spectroscopy. The non-polar fractions had good antimicrobial activities with MIC ranged between 19 - 1250 μg/ml while the polar fraction had moderate antimicrobial activities with MIC ranged between 39 - >2500 μg/ml. In general the non-polar fractions had a higher antimicrobial activity. The crude extracts contained wide range phenolic compounds with a total phenolic (7 4.91 ±1.26 to 467.04±15.82 mg GAE/g plant material), and total flavonoids (11.27±3.37 to 176±5.96 mg EQ/g plant material). The antioxidant activities were concentrated and potentiated in the polar fractions. The non-polar fractions had poor antioxidant activities with EC50 values ranging from 0.21 ±0.03 to 303.65±3.84 μg/ml for DPPH radical scavenging and 0.43±0.03 to 1709±91.44 μg/ml for ABTS radical scavenging. The crude extracts had selective COX-1 inhibitory activities ranging between 41.70 to 84.61% and had no COX-2 inhibitory activity. All the extracts tested had 15-LOX inhibitory capacity with LC50 values ranging between 0.86±0.27 and 111.44±37.28 1-μg/ml. The cytotoxicity results indicated a wide variation in toxic potential of the crude extracts with LC50 values ranging from 3.51 to 741.901-μg/ml. The BGE extracts had dual activities as spasmolytic by stimulating the spontaneous contractility and also agonised contractions induced by spasmogens but it inhibited K+ induced contraction. CVE had spasmodic activities through a multiple mechanisms inhibiting contractions induced by spasmogens and K+ in a dosedependent manner. Several bioactive xompoundswere isolated from the <i<Combretum vendae leaves, There were triterpenoids (ursol-12-en-28-oic acid, mixtures of corosolic acid and maslinic acid, and asiatic acid and arjunolic acid) as well as bibenzyls combretastatin 85-0-2'-β-D-glucopyranoside, combretastatin 81-0-2'-β-Dglucopyranoside and a flavonoid (apigenin) .. From Bauhinia galpinii the following bioactive compounds were isolated and characterized: β-3 ethoxy sitosterol, one new flavone (5, 7, 4' 5' tetrahydroxy-2'-methoxyflavone (isoetin 2'-methyl ether) or 5, 7, 2' 5' tetrahydroxy-4'-methoxyflavone (isoetin 4'-methyl ether)), 3, 5, 7, 3', 4'-pentahydroxyflavone and 3, 5, 7, 3', 4', 5'hexahydroxyflavone, quercetin-3-0-β-galactopyranoside and myriceti n-3-0-β-galactopyranoside The extraction protocol used in this work potentiated the antimicrobial activities in the non-polar fractions while antioxidant activities were potentiated in the polar fractions. This indicated that using polar solvents as extractant for treating infectious diarrhoea may not be quite effective unless some other antidiarrhoeal mechanisms are involved. Therefore, mixture of organic solvent (ethanol) and water can be recommended for broad-based activity. Bauhinia galpinii extracts had a dual- mechanism of action (prokinetic and relaxant) on gastro-intestinal motility, depending on the prevalent patho-physiological condition and Combretum vendae mediated spasmolytic effects on isolated rat ileum through multiple inhibitions of a wide range of contractile stimuli. Hence, the presence of multiple acting spasmolytic activities in the plant extract might be contributing towards its effectiveness in treating diarrhoea and abdominal spasm. The uses of these plants in traditional medicine need to be monitored closely because of the selective inhibition of COX-1 and its associated GIT injury, and the high toxicity potential of some of the extracts. Further work evaluating the antidiarrhoea mechanisms, identification and isolation of bioactive compounds, sub-acute and acute toxicity of the plant extracts is recommended. / Thesis (PhD)--University of Pretoria, 2013. / Paraclinical Sciences / unrestricted

Diarrhoea is one of the killer diseases resulting from the dehydration and loss of electrolytes through profuse and excessive excretion of loose stool. The pathoaetiologies include infections, intestinal inflammation, imbalanced intestinal oxidative homeostasis and altered motility. Treatment with oral rehydration therapy (ORT) is a key intervention especially in secretory diarrhoea as supportive therapy. Symptomatic and non-symptomatic therapies directed at treating the intestinal tissues are available. However, these conventional treatments are still not sufficient in curing diarrhoea due to their associated hazards such as the development and spread of drugresistant pathogens, changes in normal intestinal bacteria flora and potential chronic toxicity. Therapies targeted at intestinal tissue include antimotility and antisecretory agents have adverse effects such as addictiveness, constipation and fatal ischaemic colitis. Many ethnopharmacological and ethnobotanical therapies for treating diarrhoea exist among different cultures. The aims of this study were to evaluate the biological activities of plant extracts against some diarrhoeal pathophysiologies. A literature search in English of published articles and books that discussed ethnobotanical uses of medicinal plants in southern Africa was conducted. A list of 230 medicinal plants used in South African traditional medicines for treating diarrhoea and associated complications was created. The list included family, genus, species, biological activities and bioactive isolates as well as the remedies for diarrhoea. Twenty seven species were selected to evaluate for antimicrobial, antioxidant and anti-inflammatory activities. Safety of the plants was determined by determining the cytotoxicity of the crude extracts against Vero African green monkey kidney cell lines using a standard method. Motility effects of Bauhinia galpinii (BGE) and Combretum vendae (CVE) were determined by modulation of the contractility process of the isolated rat ileum induced by spasmogens. Phenolic compositions of the crude extract were determined using various standard methods and finally bioactivity guided isolation of antimicrobial and antioxidant compounds from BGE and CVE were carried out using open column chromatography. Identification and characterization of the isolated compounds was achieved by NMR, EI-MS and UV spectroscopy. The non-polar fractions had good antimicrobial activities with MIC ranged between 19 – 1250 μg/ml while the polar fraction had moderate antimicrobial activities with MIC ranged between 39 - >2500 μg/ml. In general the non-polar fractions had a higher antimicrobial activity. The crude extracts contained wide range phenolic compounds with a total phenolic (74.91±1.26 to 467.04±15.82 mg GAE/g plant material), and total flavonoids (11.27±3.37 to 176±5.96 mg EQ/g plant material). The antioxidant activities were concentrated and potentiated in the polar fractions. The non-polar fractions had poor antioxidant activities with EC50 values ranging from 0.21±0.03 to 303.65±3.84 μg/ml for DPPH radical scavenging and 0.43±0.03 to 1709±91.44 μg/ml for ABTS radical scavenging. The crude extracts had selective COX-1 inhibitory activities ranging between 41.70 to 84.61% and had no COX-2 inhibitory activity. All the extracts tested had 15-LOX inhibitory capacity with LC50 values ranging between 0.86±0.27 and 111.44±37.28 μg/ml. The cytotoxicity results indicated a wide variation in toxic potential of the crude extracts with LC50 values ranging from 3.51 to 741.90μg/ml. The BGE extracts had dual activities as spasmolytic by stimulating the spontaneous contractility and also agonised contractions induced by spasmogens but it inhibited K+ induced contraction. CVE had spasmodic activities through a multiple mechanisms inhibiting contractions induced by spasmogens and K+ in a dosedependent manner. Several bioactive xompoundswere isolated from the Combretum vendee leaves, There were triterpenoids (ursol-12-en-28-oic acid, mixtures of corosolic acid and maslinic acid, and asiatic acid and arjunolic acid) as well as bibenzyls combretastatin B5-O-2’-β-D-glucopyranoside, combretastatin B1-O-2’-β-D glucopyranoside and a flavonoid (apigenin). From Bauhinia galpinii the following bioactive compounds were isolated and characterized: P-3 ethoxy sitosterol, one new flavone (5, 7, 4’ 5’ tetrahydroxy-2’-methoxyflavone (isoetin 2’-methyl ether) or 5, 7, 2’ 5’ tetrahydroxy-4’-methoxyflavone (isoetin 4’-methyl ether)), 3, 5, 7, 3’, 4’-pentahydroxyflavone and 3, 5, 7, 3’, 4’, 5’- hexahydroxyflavone, quercetin-3-O-β-galactopyranoside and myricetin-3-O-β-galactopyranoside. The extraction protocol used in this work potentiated the antimicrobial activities in the non-polar fractions while antioxidant activities were potentiated in the polar fractions. This indicated that using polar solvents as extractant for treating infectious diarrhoea may not be quite effective unless some other antidiarrhoeal mechanisms are involved. Therefore, mixture of organic solvent (ethanol) and water can be recommended for broad-based activity. Bauhinia galpinii extracts had a dual- mechanism of action (prokinetic and relaxant) on gastro-intestinal motility, depending on the prevalent patho-physiological condition and Combretum vendee mediated spasmolytic effects on isolated rat ileum through multiple inhibitions of a wide range of contractile stimuli. Hence, the presence of multiple acting spasmolytic activities in the plant extract might be contributing towards its effectiveness in treating diarrhoea and abdominal spasm. The uses of these plants in traditional medicine need to be monitored closely because of the selective inhibition of COX-1 and its associated GIT injury, and the high toxicity potential of some of the extracts. Further work evaluating the antidiarrhoea mechanisms, identification and isolation of bioactive compounds, sub-acute and acute toxicity of the plant extracts is recommended. / Thesis (PhD)--University of Pretoria, 2012. / Paraclinical Sciences / unrestricted

Au début de ce doctorat, plusieurs études avaient identifié l'intestin grêle, siège de l'absorption du glucose, en tant que premier organe impliqué dans le contrôle de l'homéostasie glucidique lors d'un repas. En particulier, il a été démontré que la détection entérique de glucose permettait d'impacter son utilisation par le muscle et le foie, via un relai central impliquant une libération hypothalamique de monoxyde d'azote (NO). De plus, notre groupe a également démontré qu'une altération de la détection entérique du glucose, associée à une réponse neuronale hypothalamique anormale, participait à la mise en place d'un Diabète de Type 2 (DT2). En plus de ces problèmes de détection de nutriments, les patients obèses et diabétiques souffrent de troubles de la motilité intestinale (en particulier d'une hypercontractilité intestinale), liés à une atteinte du Système Nerveux Entérique (SNE). En effet, ce dernier est constitué d'environ 600 millions de neurones interconnectés chez l'Homme, contrôlant les contractions des muscles lisses intestinaux. D'un point de vue régulation, le SNE communique en permanence avec le Système Nerveux Central (SNC) via des voies nerveuses afférentes et efférentes. L'équipe s'intéresse au rôle de l'apeline en tant que nouvelle cible thérapeutique potentielle pour traiter le DT2. En particulier, notre équipe a récemment montré que l'apeline était libérée par les entérocytes dans la partie proximale de l'intestin, et qu'à ce niveau elle contrôlait l'absorption intestinale du glucose. Cependant, le fait que l'apeline puisse également cibler les neurones du SNE, et donc moduler la contractilité intestinale, n'était pas encore démontré. Lors de ce travail de thèse, nous avons ainsi pu montrer qu'en fonction de sa concentration, l'apeline activait des populations neuronales entériques différentes provoquant une stimulation ou, au contraire, une inhibition des contractions duodénales. La stimulation de cette contractilité duodénale par de faibles concentrations d'apeline entraîne une augmentation de l'absorption intestinale de glucose, mais également une diminution de la libération de NO hypothalamique, aboutissant à une moindre utilisation de ce dernier par le muscle squelettique. A l'inverse, de fortes concentrations d'apeline sont associées à une diminution de cette activité duodénale, entraînant un retour de l'ensemble de ces paramètres à des niveaux contrôles. Dans un second temps, nous avons voulu tester si cette motilité duodénale pouvait être considérée comme une cible thérapeutique pour traiter le DT2. Pour cela, nous avons effectué un traitement oral quotidien, pendant une semaine, avec la concentration d'apeline capable de diminuer l'activité duodénale, chez des souris obèses-diabétiques. Cette stimulation chronique par l'apeline permet de restaurer la contractilité duodénale de ces souris diabétiques au même niveau que celle de souris saines. De plus, cet effet est associé à une amélioration de leur tolérance au glucose ainsi que leur index de résistance à l'insuline. Ainsi, ce doctorat a permis de décrire un nouveau mode de communication entre l'intestin et le cerveau dans le contrôle de l'homéostasie glucidique. En effet, moduler les contractions duodénales en modifiant l'activité du SNE permettrait non seulement d'impacter l'absorption intestinale de glucose, mais également d'activer un axe duodénum-hypothalamus aboutissant au contrôle de l'utilisation périphérique de glucose. Dès lors, ce couplage " SNE-contraction duodénale " représenterait une cible thérapeutique prometteuse dans le traitement de maladies métaboliques telles que le DT2. / Prior to this PhD, several studies had determined that the small intestine, the site of glucose absorption, is the first organ involved in the control of glucose homeostasis during food intake. In particular, enteric glucose detection has been demonstrated to impact its utilization by muscles and liver, via a central relay involving hypothalamic nitric oxide (NO) release. Moreover, our group has also demonstrated that an alteration of enteric glucose detection, associated with an abnormal hypothalamic neuronal response, participates in type 2 diabetes (T2D) development. In addition to these defaults of nutrients detection, obese and diabetic patients suffer from intestinal motility disorders (in particular intestinal hypercontractility), linked to an alteration of the Enteric Nervous System (ENS). The ENS is composed of 600 million interconnected neurons in humans, known to control intestinal smooth muscles. The ENS permanently communicates with the Central Nervous System (CNS) via afferent and efferent nervous messages. Our team studies the role of apelin as a new potential therapeutic target to treat T2D. In this context, our group has recently demonstrated that apelin is released by the enterocytes in the proximal part of the intestine. At this site, apelin controls intestinal absorption of glucose. However, it hadn't been addressed yet whether apelin is also able to target enteric neurons, and consequently modulate intestinal contractility. During this PhD, we have highlighted that, depending of its concentration, apelin activates different enteric neuronal populations, leading to stimulation or, on the contrary, inhibition of duodenal contractions. Stimulation of this duodenal contractility by low concentrations of apelin causes an increase in intestinal glucose absorption, but also a decrease in hypothalamic NO release, leading to a reduced utilization of glucose by skeletal muscle. Conversely, high concentrations of apelin are associated with a decrease in the duodenal activity, leading to the restoration of all these parameters at basal levels. Then, we wanted to test whether duodenal motility could be considered as a therapeutic target to treat T2D. We performed a daily oral treatment, during one week, with the concentration of apelin able to decrease duodenal activity in obese and diabetic mice. We have shown that this chronic apelin treatment restores duodenal contractility in diabetic mice, at a similar level to that observed in normal mice. Moreover, this effect is associated with an improved glucose tolerance and insulin resistance index. Thus, this PhD describes a new mode of communication between the intestine and the brain, in the control of glucose homeostasis. Indeed, the modulation of duodenal contraction by targeting ENS activity could not only impact intestinal glucose absorption, but also activate a duodenum-hypothalamus axis, leading to the control of peripheral glucose utilization. Consequently, the "ENS-duodenal contraction" coupling could represent a promising therapeutic target to treat metabolic diseases such as T2D.

Parkinson’s disease is a neurodegenerative disease resulting primarily from loss of dopaminergic innervation in the striatum subsequent to cell loss in the substantia nigra pars compacta. The abnormal accumulation of the normal pre-synaptic protein α-synuclein (αsyn) forms intraneuronal inclusions known as Lewy neurites and Lewy bodies. The origins of central Lewy pathology have been suggested to lie in the enteric nervous system, ascending through the vagus nerve to the dorsal motor nucleus of the vagus. To ascertain gastrointestinal regions most likely to be the source of central Lewy pathology, αsyn expression was evaluated in the neural elements of gastrointestinal regions receiving the densest vagal innervation. The vermiform appendix was found to have the densest αsyn-immunoreactive innervation in all layers of the gut wall. In addition, macrophages in the appendiceal mucosa were laden with αsyn within lysosomes, consistent with attempts to prevent the spread of disease or to correct synaptic dysfunction.

No description available.

Die Stamm- und Vorläuferzellen, im Weiteren als Progenitoren bezeichnet, des humanen Darms treten seit einigen Jahrzehnten immer stärker in den Fokus der Forschung. Mit der Entdeckung von Progenitorzellen im zentralen Nervensystem in den 60er Jahren des 20. Jahrhunderts kamen auch Bestrebungen auf, im peripheren Nervensystem nach Progenitoren zu suchen. Bald darauf, zu Beginn des 21. Jahrhunderts, wurden Sie entdeckt. Diese Population von Zellen bietet eine vielversprechende Möglichkeit, aus adultem Darmgewebe Progenitorzellen zu isolieren und diese therapeutisch, bei einer Vielzahl gastroenterologischer Erkrankungen, autolog einzusetzen. Derzeit werden auch andere mögliche Stamm- und Vorläuferzellen evaluiert. Die vorliegende Arbeit liefert einen wichtigen Beitrag zur Charakterisierung humaner, enterischer, neuraler Progenitorzellen. Dies ist essentiell für eine mögliche, klinische Translation. Es gelang, die in vitro Kulturbedingungen der isolierten, humanen Zellen durch Wachstumsfaktorenzugabe und Supplemente zu verbessern und ermöglicht so auch ein besseres Verständnis der in vivo-Situation. Weiterhin wurde das sich verändernde enterische Nervensystem des humanen Darms, in verschiedenen Altersstufen, spezifisch isoliert und analysiert. Es konnten neuartige Befunde zum Verlust von neuronalen Zellen im Allgemeinen und der charakteristische Verlust von NOS-Neuronen im Speziellen erhoben werden. Erstmals beobachtet wurde die Erhöhung der Genexpression für Gliazellen im gealterten ENS. Die gewonnen Erkenntnisse wurden weiterhin in einer in vivo-Transplantationsstudie angewendet. In ein Mausmodell mit einem chemisch geschädigten Darmnerensystem wurden postnatale, humane Progenitoren eingebracht und es gelang der Beweis einer verbesserten Funktionalität durch Integration von neugebildeten Neuronen, Glia und Muskelzellen.