Submitted by Haroudo Xavier Filho (haroudo.xavierfo@ufpe.br) on 2016-04-14T18:22:12Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação -Marciana S_ F_ Cordeiro _1_.certa.pdf: 3647564 bytes, checksum: f459470e06543d55f9f637a82005d075 (MD5) / Made available in DSpace on 2016-04-14T18:22:12Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Dissertação -Marciana S_ F_ Cordeiro _1_.certa.pdf: 3647564 bytes, checksum: f459470e06543d55f9f637a82005d075 (MD5) Previous issue date: 2015-02-25 / CNPq / O cloridrato de pilocarpina vem sendo utilizado no tratamento da xerostomia, entretanto sua atuação sistêmica promove reações adversas indesejáveis. Contudo, os atuais sistemas de liberação prolongada de fármacos, podem controlar variações de concentração plasmática e reduzir estes efeitos colaterais. Adicionalmente, a obtenção de comprimidos mucoadesivos associado a este sistema de liberação favorece a ação prolongada do fármaco na cavidade oral, trazendo benefícios importantes para o tratamento. Assim, este trabalho tem como objetivo o desenvolvimento de comprimidos mucoadesivos a base de cloridrato de pilocarpina para o tratamento da xerostomia, utilizando para este propósito a mistura física da goma do cajueiro/pilocarpina, quitosana/pilocarpina, mistura física de ambos os polímeros com pilocarpina e desenvolvimento de uma blenda polimérica por liofilização contendo goma de cajueiro e quitosana. Inicialmente a compatibilidade fármaco-polímero foi avaliada através da Calorimetria Exploratória Diferencial (DSC), Termogravimetria (TG), Espectroscopia de Infravermelho (IV) e Difração de Raios-X (DRX). Em seguida, foram obtidos comprimidos por compressão direta. Os comprimidos obtidos foram submetidos ao controle de qualidade, avaliação mucoadesiva e perfil de liberação. Na avaliação da mistura física (MF) dos polímeros/pilocarpina e da blenda/pilocarpina não foram encontrados sinais de incompatibilidades diante da avaliação pelas técnicas de DSC e TG. Dentre as formulações desenvolvidas, a blenda/pilocarpina demonstrou agregar propriedades mucoadesivas e retardo na liberação do fármaco, propriedades estas não encontradas nos polímeros individualmente e na mistura física/pilocarpina. A blenda/pilocarpina apresentou liberação de 53% do fármaco no tempo 180 min., tempo de mucoadesão de 510 min e incremento da força de mucoadesão. Esses resultados mostram o potencial do sistema polimérico para futuros desenvolvimentos na área farmacêutica. / The pilocarpine hydrochloride has been used in the treatment of xerostomia, however its systemic activity promotes undesirable side effects. However, the current prolonged release of drugs can control variations in plasma concentration and reduce these side effects. Additionally, to obtain tablets mucoadhesive associated with this delivery system favors prolonged drug action in oral cavity, which has important benefits for treatment. This work aims to develop mucoadhesive tablets pilocarpine hydrochloride base for the treatment of xerostomia, using for this purpose the physical mixture of cashew gum/pilocarpine, chitosan/pilocarpine, physical mixture of both polymers with pilocarpine and development of a polymer blend by lyophilization containing cashew gum and chitosan. Initially the drug-polymer compatibility was evaluated by Differential Scanning Calorimetry (DSC), thermogravimetry (TGA), Infrared Spectroscopy (IR) and X-ray Diffraction (XRD). Then, tablets were obtained by direct compression. The tablets were subjected to quality control, mucoadhesive evaluation and release profile. In assessing the physical mixture (MF) of the polymers / pilocarpine and blend / pilocarpine were not incompatible signals found on the evaluation by DSC and TG techniques. Among the developed formulations, the blend / pilocarpine shown add mucoadhesive properties and delayed drug release, these properties not found in polymers individually and physical / pilocarpine mixture. The blend / pilocarpine showed 53% release of the drug in time 180 min. Mucoadhesion time of 510 min, and increased strength mucoadhesion. These results show the potential of the polymer system for future developments in the pharmaceutical field.

Orientador: Cláudio Aparecido Casatti / Resumo: As teneurinas (Tens) são proteínas transmembrana do tipo II, constituídas de quatro membros homólogos (Ten-1-4). Estas proteínas são expressas principalmente durante a neurogênese do sistema nervoso central (SNC) e estão envolvidas primariamente no estabelecimento dos circuitos neuronais. Tens apresentam vários sítios de clivagens intracelular e extracelular que resultam em peptídeos bioativos, destacando-se os peptídeos associados aos terminais carboxila das teneurinas (Teneurin C-terminal-Associated Peptides, TCAPs). As latrofilinas (LPHN1-3) representam receptores associados à proteína G, sendo os principais receptores endógenos das Tens. A interação da Ten-2 com a LPHN-1 resulta na modulação nos níveis de cálcio intracelular, fato este que pode estar desbalanceado durante episódios epileptogênicos. O principal propósito deste estudo foi verificar possíveis alterações na imunorreatividade e na expressão gênica da Ten-2 no SNC em um modelo de epilepsia induzida por cloreto de lítio-cloridrato de pilocarpina em ratos adultos. Adicionalmente, as expressões gênicas do TCAP-2 e LPHN1 também foram analisadas, visto que são as principais proteínas correlacionadas à Ten-2. Para isto, ratos adultos (Rattus norvegicus; n=49) foram submetidos a indução de status epilepticus (SE) com cloreto de lítio (127 mg/kg) e cloridrato de pilocarpina (40 mg/kg) e divididos em grupos controles, grupos 2, 5 e 14 dias após SE e grupos epilepsia crônica (35 e 75 dias). Amostras do SNC destes animais... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Teneurins (Tens) are a type II transmembrane protein family composed of four homologous members (Ten-1-4). These proteins are primarily present in the central nervous system (CNS) during neurogenesis and exert an important role in the development and establishment of neuronal circuits. Tens have several intra- and extracellular cleavage sites, originating bioactive peptides, such as the carboxyl-terminal peptides named Teneurin C-terminal-Associated Peptides (TCAPs). Latrophilins (LPHN1-3) represent G protein-coupled receptors and are considered the main endogenous receptors for Tens. The Ten-2-LPHN-1interaction results in intracellular calcium modulation in neurons and this system can be changed during epilepsy induction. The main purpose of this study was to verify possible alterations in immunoreactivity and gene expression of Ten-2 in the CNS from an adult rat model of lithium chloridepilocarpine-induced epilepsy. In addition, TCAP-2 and LHPN1 gene expressions were also analyzed, as they are the main Ten-2 related proteins. For this, adult male (Rattus norvegicus; n = 49) were submitted to status epilepticus (SE) induced by intraperitoneal administration of lithium chloride (127 mg/kg) and pilocarpine hydrochloride (40 mg/kg). Subsequently, the animals were divided into control groups, 2-, 5- and 14-day groups after SE, as well as chronic epilepsy group (35-75 days). Samples were submitted to immunohistochemistry technique to identify Teneurin-2-like immunoreactive (Ten-2... (Complete abstract click electronic access below) / Doutor

Neonatal destruction of rat nigrostriatal dopaminergic fibers results in an enhanced oral activity response to both dopamine (DA) D1 and serotonin (5-HT) agonists. Because cholinergic systems represent another one of the neural circuits involved in oral behavior, it was of interest to determine whether muscarinic receptors might also be sensitized in the lesioned rats. At 3 days after birth, rats were pretreated with desipramine HCl (20 mg/kg, IP) 1 h before 6-hydroxydopamine (6-OHDA) HBr (100 μg in each lateral ventricle) or saline-ascorbic acid (0.1%) vehicle. Between 2 and 4 months, behavioral supersensitivity to a D1 agonist (SKandF 38393) and 5-HT agonist (m-chlorophenylpiperazine; m-CPP) was established before rats were challenged with the muscarinic receptor agonist, pilocarpine HCl (0.125 to 10.0 mg/kg, IP). The pilocarpine dose-effect curve was shifted to the left, with a maximal effect of 63.7 ± 8.6 oral movements being produced by a 1.0 mg/kg pilocarpine HCl dose in the 6-OHDA lesioned rats, versus 15.0 ± 2.4 oral movements in the control group (p < 0.001). The enhanced response to pilocarpine was attenuated by the muscarinic receptor antagonist, scopolamine HCl (0.1 mg/kg IP). These findings indicate that neonatal 6-OHDA treatment produces supersensitization of muscarinic receptors in rats.

No description available.

L’épilepsie du lobe temporal (ELT) est une pathologie neurologique sévère dont le fort taux de pharmacorésistance nécessite de nouveaux traitements. Le modèle lithium-pilocarpine modélise les caractéristiques et le développement de l’ELT. L’administration du carisbamate au début de l’épileptogenèse empêche l’apparition de l’ELT dans une sous-population de rats et la remplace par une épilepsie de type absence (ETA). L’évaluation cognitive effectuée durant la phase chronique a permis de distinguer les deux sous-populations : le groupe épilepsie de type absence ne développe pas le déficit cognitif sévère observé dans le modèle lithium pilocarpine. La spectroscopie du 13C n’a pas révélé de différence métabolique majeure entre les deux sous populations traitées, qu’elles développent une ELT ou une ETA. Ce travail souligne que l’administration précoce de carisbamate peut transformer l’ELT en une épilepsie moins sévère et fortement améliorer les comorbidités cognitives qui accompagnent l’ELT. / Temporal lobe epilepsy (TLE) is a severe neurological disease with a high refractory rate, which requires new treatments. The lithium-pilocarpine model allows reproducing human TLE features and development. Carisbamate administration at epileptogenesis onset prevents TLE incidence in a rats’ subpopulation, which is substituted by absence-like epilepsy (ALE). Behavioral and cognitive assessment performed during chronic period allowed differentiating the two subpopulations: ALE group did not develop the severe cognitive impairment shown in the lithium-pilocarpine model. 13C spectroscopy did not show major metabolism difference between the two treated subpopulations, whatever they develop TLE or ALE. This work demonstrates that early carisbamate administration can induce a shift from TLE in a less severe epilepsy form, and can strikingly improve TLE-related cognitive comorbidities.

L’épilepsie du lobe temporal (ELT) est la forme d’épilepsie partielle la plus fréquente chez l’adulte. Elle se caractérise par une période de latence pendant laquelle l’ELT se met en place. Cette période est appelée épileptogenèse. L’épileptogenèse reste une période inaccessible chez l’Homme. Cependant, les modèles animaux présentent l’avantage de pouvoir l’étudier, dans le but de prévenir l’ELT. Ainsi, mon travail de thèse a consisté à mettre en évidence des marqueurs prédictifs de l’épileptogenèse, sur le plan cognitif et électrophysiologique in vivo, à partir du modèle pilocarpine. Les résultats ont montré que dès le stade précoce de l’épileptogenèse, des déficits de mémoire spatiale corrélaient avec une diminution de la puissance des oscillations thêta chez les animaux pilocarpine, sans modification jusqu’au stade chronique. Au même stade, une diminution de la puissance et de la fréquence des oscillations thêta lors du comportement d’exploration a été observée. L’activité interictale, activité paroxystique présente chez les patients entre leurs crises et caractéristique du stade épileptogène dans les modèles animaux, ne corrèle pas directement avec les déficits cognitifs mais diminue la puissance des oscillations thêta dans l’onde après la pointe au cours de l’épileptogenèse mais plus au stade chronique, ce qui suggère une importante modification du réseau avant le stade chronique. On a également décrit deux types d’activité interictale dont les propriétés (amplitude, nombre) et la dynamique au cours du temps sont modifiées juste avant la première crise spontanée, ce qui pourrait constituer, comme les déficits spatiaux et l’altération du rythme thêta, un marqueur prédictif de l’épileptogenèse. De plus, une augmentation du couplage entre l’hippocampe et le CE est observée au cours de l’épileptogenèse mais plus au stade chronique, alors qu’une modification du flux de l’information entre ces deux structures au stade épileptogène précoce persiste jusqu’au stade chronique, indépendamment de la présence ou non d’activité interictale. Ces résultats mettent en évidence la construction d’un réseau épileptogène, un changement majeur du réseau avant la première crise spontanée, et des marqueurs qui pourraient être prédictifs de l’épileptogenèse. L’ELT, les oscillations et les fonctions cognitives faisant intervenir des propriétés de réseau, tels les processus de synchronisation, l’enregistrement de 15 structures au sein du lobe temporal a montré, à partir du modèle pilocarpine, un réseau doté de caractéristiques plus « small-world » (SW) qui tendrait à se synchroniser plus localement, avec une perte des connexions longue distance. Ces résultats pourraient expliquer les altérations de réseau observées précédemment au cours de l’épileptogenèse. L’analyse SW et de cohérence, à l’échelle de ce réseau de structures, lors de différents états (comportementaux, processus cognitifs), mettent en évidence des changements de la dynamique lors de ces états, en conditions normales et pathologiques. Toutes ces modifications de réseau doivent être sûrement recrutées dans la mise en place d’un cerveau épileptique et des altérations cognitives associées. / Temporal lobe epilepsy (TLE) is the most common form of partial epilepsy in adults. TLE is characterized by a latent period during which TLE takes place. This period is called epileptogenesis. In TLE patients, epileptogenesis is unexplored. However, the use of animal models, like pilocarpine model, allows the study of epileptogenic processes, in order to try to prevent TLE. Thus, my PhD work tries to yield some predictive markers of epileptogenesis, in the pilocarpine model. We studied cognitive and electrophysiological in vivo alterations in this model. We showed that there are early and persistent spatial deficits that correlate with a decrease of the power of theta oscillations, i.e. during the early stage of epileptogenesis and the chronic stage. At the same time, there is also a decrease of power and frequency of theta rhythm during exploratory behaviors. Interictal-like activity (ILA) is a pathological activity present during epileptogenesis in experimental models. ILA does not correlate with cognitive deficits, but decreases theta power after the spike, i.e. in its wave, during epileptogenesis but not during the chronic stage anymore. This suggests an important network alteration before the chronic stage. Indeed, we described two types of ILA, whose properties (number, amplitude) and dynamics evolved during epileptogenesis with a major switch just before the first spontaneous seizure. All together, these results may constitute, with spatial deficits and theta rhythm alterations, predictive markers of epileptogenesis. Moreover, we showed an increase in the coupling, ILA-dependent, between the hippocampus and the entorhinal cortex, during epileptogenesis but not during the chronic stage, whereas a reversal of the information flow between these two structures occurs at the early stage of epileptogenesis and persists without any modification till the chronic stage. These results suggest the build-up of an epileptogenic network, a major switch of network properties just before the first spontaneous seizure, and some markers that could be predictive of epileptogenesis. TLE, oscillations and cognition involved processes at the network level, in particular synchronization processes. These processes could be possible via oscillations, which allow information transfer between structures of the network, in order to provide behavioral and cognitive processing. Recordings performed in 15 different structures of the temporal lobe showed, in pilocarpine animals, a network with more “small-world” (SW) features, with a higher local clustering and a loss of long-range connections. These results could explain cognitive and oscillatory alterations observed previously during epileptogenesis. SW and coherence analysis, at the network level, between signals during different brain-states (behaviors and cognitive processes) showed changes in dynamics occurring during these states, in normal and epileptogenic conditions. All these modifications in network activities may be involved in the construction of an epileptic brain and in associated cognitive deficits.

Organophosphates (OPs) are a major class of pesticides and nerve agents that elicit acute toxicity by inhibiting acetylcholinesterase (AChE), the enzyme responsible for the degradation of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Acetylcholine accumulation following extensive AChE inhibition leads to an acute cholinergic syndrome characterized by autonomic dysfunction, involuntary movements, muscle fasciculations, respiratory distress, and seizures. Despite their classification as moderate to highly toxic, OP pesticides are the most widely used class of insecticides in the U.S., and are even more commonly used worldwide. Additionally, there is a growing concern that OP nerve agents could be used to cause mass civilian casualties. It is well known that the survivors of acute nerve gas poisoning and chronic OP pesticide exposure exhibit neurobehavioral deficits including mood changes, depression, and memory impairments. Despite this, there are very few treatments available for OP-intoxication survivors and this topic is under-researched. In this study we investigated whether animals surviving a single severe OP exposure exhibited long-term neurological impairments, using two OP agents: paraoxon (POX) and diisopropyl fluorophosphates (DFP), as well as a non-OP chemoconvulsant, pilocarpine (Pilo), which acts as a muscarinic agonist. Exposure to POX, DFP, or Pilo led to overt signs of cholinergic toxicity. POX and DFP rats were rescued with an optimized atropine, 2-PAM, and diazepam therapy per current OP-exposure treatment guidelines, while Pilo rats were given only diazepam. Saline was administered to control rats at all pharmacological timepoints. Surviving rats were studied using established behavioral assays for identifying symptoms of depression and memory impairment 3-6 months after exposure to toxic agents. In the forced swim test, POX, DFP, and Pilo animals exhibited increased immobility time indicative of a despair-like state. In the sucrose preference test, POX, DFP, and Pilo rats did not display a preference for sucrose water, indicating an anhedonia-like condition. POX, DFP, and Pilo rats also displayed increased anxiety as characterized by significantly lower performance in the open arm of the elevated plus maze. Furthermore, when tested with a novel object recognition paradigm, POX, DFP, and Pilo rats exhibited a significantly lower discrimination ratio, indicating impaired recognition memory. The results indicate that these models of survival from severe POX and DFP exposure can be employed to study chronic behavioral and cognitive comorbidities and to further investigate the molecular bases for these comorbidities, potentially leading to the development of pharmacological therapies.

These studies were completed to examine how status epilpeticus seizure characteristics are modulated during post-juvenile brain development. This may determine if postnatal age in rats is a better identifier of stages of post-juvenile brain development. The first study fully detailed the acute discrete seizure phase of the rat pilocarpine-SE model. Results for this study showed that Racine behavioral severity score, spike frequency, and seizure severity during the acute discrete seizure phase change in relation to post-juvenile brain developmental stages. The second study fully detailed early and late patterns of status epilepticus. Results for this study displayed modulation of time in pattern, spike frequency, and relative delta power for seizure pattern during post-juvenile ages. The third study displayed modulation of diazepam efficacy during post-juvenile ages. The data suggest characteristics in the acute discrete seizure pliase, chronic SE phase, and therapeutic window of SE change in relation to age during post-juvenile brain development. This establishes that age is a better estimator of developmental stage than animal bodyweight.

Introdução: A esquizofrenia é um dos principais transtornos mentais e promove distúrbios comportamentais e cognitivos. Apesar do grande impacto social, pouco se conhece sobre a patofisiologia e etiologia da esquizofrenia. Pacientes com desordens psicóticas têm aumentado risco de desenvolver epilepsia, e pacientes com epilepsia do lobo temporal tem alta frequência de psicoses. A utilização de modelos experimentais animais de esquizofrenia e epilepsia pode ajudar a entender a neurobiologia dessas doenças e ter papel importante no desenvolvimento de novas estratégias terapêuticas. As interações complexas das crises epilépticas e quadros psicóticos tem sido aos poucos desvendadas. O óxido nítrico (NO) é um importante modulador da neurotransmissão e doadores de NO como o nitroprussiato de sódio (NPS) tem efeitos promissores em pacientes com esquizofrenia. Em modelos animais de epilepsia, NO pode ter efeito pró ou anticonvulsivante, sugerindo que o uso de NPS em pacientes com epilepsia e psicose pode não ser tão simples. Objetivos: Desenvolver um modelo animal de epilepsia e psicose comórbida, e compará-lo do ponto de vista comportamental e neuropatológico com modelos animais puros de epilepsia e esquizofrenia. Além disso, verificar a possível modulação desencadeada pelo tratamento com NPS nos modelos citados. Metodologia: Ratos Wistar machos (260-300g) foram divididos em grupos controle (SAL+SAL), epilepsia puro (PILO+SAL), esquizofrenia (SAL+QUET), epilepsia e psicose comórbida (PILO+QUET) e suas versões tratadas com NPS (SAL+SAL+NPS, PILO+SAL+NPS, SAL+QUET+NPS e PILO+QUET+NPS). Esses animais foram avaliados em diferentes aspectos comportamentais (campo aberto, teste de inibição pré- pulso, memória de reconhecimento de objeto e memória de trabalho), e filmados ao longo de 71 dias para o monitoramento de crises epilépticas espontâneas recorrentes. Também foram avaliadas a perda neuronal e a expressão de nNOS em diferentes regiões cerebrais. Resultados: NPS reduziu a frequência de crises nos animais com epilepsia e psicose comórbida quando comparados a animais não tratados. NPS também teve efeito ansiolítico no modelo animal de epilepsia com e sem psicose, e diminuiu os correlatos comportamentais de sintomas positivos dos animais no modelo de psicose e no de epilepsia + psicose, além de reverter o prejuízo no filtro sensório motor nos animais que receberam pilocarpina e quetamina. No reconhecimento de objeto o modelo de epilepsia e epilepsia+psicose o tratamento com NPS não interferiu no desempenho de memória de curto prazo, porém NPS melhorou a memória de longo prazo no modelo de psicose. NPS preservou regiões como o córtex entorrinal e subiculum nos animais epilépticos, mas a camada granular e córtex pré-límbico revelaram perda significativa nos animais controles. Alta expressão de nNOS em diferentes regiões cerebrais foram visualizadas nos animais com epilepsia, com destaque para aqueles que receberam tratamento com NPS. Conclusão: O tratamento com NPS foi efetivo na amenização de sintomas correlatos comportamentais de psicose no modelo puro de esquizofrenia e no comórbido VIII com epilepsia. Além disso, não exacerbou crises e contribuiu para diminuição delas nos animais do modelo de epilepsia e psicose, que apresentou grandes similaridades com o que é encontrado em casos clínicos. Nossos resultados sugerem que o uso do NPS pode ter resultados na melhoria dos sintomas da psicose interictal humana, assim como já observado para a esquizofrenia. / Introdution: Schizophrenia is a major mental disorder that affects 1% of young adults and has a great impact on quality of life, behavior, and cognition. Despite the high social burden, little is known about the pathophysiology and etiology of schizophrenia. Patients with psychotic disorders have increased risk of developing epilepsy, and patients with temporal lobe epilepsy have a high frequency of psychoses. The use of experimental animal models of epilepsy and schizophrenia may help to better understand the neurobiology of these diseases and play an important role in the development of potential new therapeutic strategies. The complex interactions of seizures and psychotic symptoms are being unveiled. Nitric oxide (NO) is an important modulator of neurotransmission and NO donors such as sodium nitroprusside (SNP) have shown promising effects in schizophrenic patients. In animal models of epilepsy, NO may exert pro- or anticonvulsant effects, suggesting that the use of SNP in patients with epilepsy and psychosis may not be so straightforward. Objectives: To develop an animal model of epilepsy and comorbid psychosis, and compare it from the behavioral and neuropathological point of view with pure animal models of epilepsy and schizophrenia. It was hoped, to verify the possible modulation triggered by the treatment with SNP. Metodology: Males Wistar rats weighing 260-300g were divided in controls group (SAL+SAL), pure epilepsy (PILO+SAL), schizophrenia (SAL+QUET), comorbid psychosis (PILO+KET) and their versions treated with SNP (SAL+SAL+SNP, PILO+SAL+SNP, SAL+KET+SNP and PILO+KET+SNP). These animals were evaluated in a variety of behavioral tests (open field, prepulse inhibition startle reflex, object recognition and working memory), and were filmed over 71 days to monitor spontaneous recurrent seizures. We also evaluated neuronal loss and nNOS expression in different brain regions. Results: SNP reduced seizure frequency in animals with epilepsy and psychosis when compared to those not treated with SNP. SNP also showed anxiolytic effects in the animal model of epilepsy with or without psychosis, decreased behavioral correlates of positive symptoms in the animal model of epilepsy + psychosis, and prevented sensorimotor gating deficits in epilepsy + psychosis IX model, The object recognition test showed that in epilepsy and epilepsy + psychosis models the treatment with SNP did not interfere with short-term memory performance, but SNP improved long-term memory in the psychosis model. SNP preserved brain regions like entorhinal cortex and subiculum in epileptic animals, but the granular layer and prelimbic cortex revealed significant loss in controls animals. High expression of NOS in same brain regions was observed in the animal model of epilepsy, especially in the animals receiving SNP. Conclusion: Treatment with SNP was effective in ameliorating symptoms of behavioral correlates of psychosis in the pure model of schizophrenia and the model comorbid with epilepsy. Moreover, SNP did not exacerbate seizures and reduced seizure frequency in the animal model of epilepsy + psychosis, which showed striking similarities to clinical cases. Our results suggest that the use of SNP could ameliorate symptoms of human interictal psychosis, such as those observed in schizophrenia.

Diabetes mellitus is associated with several clinically significant abnormalities in the oral cavity and salivary glands, the most common being periodontitis, salivary gland enlargement and a sensation of dry mouth. The pre­valence of dental caries in diabetics is mostly reported to be decreased or unaffected. Since there is a shortage of information concerning the influence of metabolic control and duration of diabetes on these abnormalities, the present studies were performed. Three-month-old rats were made alloxan-diabetic and investigated after one and twelve months’ duration of dia­betes for oral lesions and feeding behavior. They had free access to a standard pellet diet and tap water. Strepto­coccus mutans and lactobacilli were naturally occurring. In diabetic rats the proportion of the oral flora which was lactobacilli was positively correlated to the blood glucose level. Untreated long-term alloxan-diabetic rats de­veloped advanced periodontal disease and root surface caries in the molars at sites of interdental impaction of foreign material. The degree of alveolar bone loss was positively correlated to the blood glucose level. Diabetic rats were hyperphagic and had a longer total eating time, including day-time eating, mainly by having longer meals but no significant increase of meal frequency, as compared with non-diabetic animals. The untreated al­loxan-diabetic rats developed reduced salivary gland weight which was of the same degree in short- and long­term diabetic animals. Short- and long-term untreated alloxan-diabetic rats showed a similar degree of morpho- metrically estimated lipid accumulation in the acinar cells of the submandibular glands, and the degree was posi­tively correlated to the blood glucose level. However, lipid inclusion occurred only in rats with a morning non­fasting blood glucose level exceeding 15 mmol/L. The capillaries in the submandibular glands of the untreated long-term alloxan-diabetic rats had a significantly increased thickness of the basement membranes as compared with the observations in short-term diabetic and non-diabetic rats. Untreated alloxan-diabetic rats were also shown to have a decreased salivary flow rate compared with non-diabetic rats, and the decreased flow was negatively correlated to the blood glucose concentration. Salivary flow rate increased with the duration of the disease. The diabetic rats had increased salivary glucose levels, which were positively correlated to blood glucose values when the latter were above 15 mmol/L, suggesting a threshold mechanism for salivary glucose excretion. Insulin therapy reversed salivary flow rate and salivary glucose concentrations toward normal. Salivary investigations were performed in eleven diabetic patients on two occasions with different metabolic con­trol. Salivary flow rate showed marked interindividual differences but was not significantly changed by improv­ed metabolic control although several of the patients initially had severely deranged glucose metabolism. A posi­tive correlation between the glucose concentration in blood and saliva was seen in the parotid saliva during secre­tory stimulation. No significant change in electrolytes, amylase or antimicrobial factors was found. / <p>S. 1-48: sammanfattning, s. 49-90: 5 uppsatser</p> / digitalisering@umu