Trauma to the central nervous system (CNS) results in an irreversible disruption of axon tracts, often leading to lifelong functional deficits. Despite a large body of research into the mechanisms that underlie the lack of axonal regeneration after CNS injury, there are currently no effective treatments. One major obstacle involves the presence at injury sites of CNS growth-inhibitory molecules, such as myelin proteins and astrocyte-derived chondroitin sulfate proteoglycans (CSPGs), which act as environmental barriers to axonal regeneration. Our lab recently described the identification and characterization of a novel compound, F05, which promotes growth on inhibitory substrates in vitro. I show that F05 improves regeneration in vivo after acute sensory axon transection as well as after optic nerve crush injury. F05 does not target known signaling molecules involved in CSPG or myelin mediated inhibition but does affect growth cone microtubule dynamics, suggesting a potentially novel mechanism of growth promotion. Using a protein microarray, I show that apoptotic signaling pathways may underlie glial-derived inhibition and its relief by F05. In addition, I employed a comparative gene microarray to show that F05 induces similar changes in gene expression as antipsychotics of the piperazine phenothiazine structural class (PhAPs). Indeed, PhAPs share F05’s ability to overcome glial-derived inhibition of cultured CNS neurons and do so through a mechanism dependent on antagonism of calmodulin. These studies have led to the identification of potentially novel clinical treatments for CNS injury as well as a better understanding of environmentally derived growth-inhibitory signaling mechanisms.

Cognitive dysfunction is a core characteristic of schizophrenia, which can often persist when other symptoms, particularly positive symptoms, may be improved with drug treatment. The non-competitive NMDA receptor antagonist, phencyclidine (PCP), is a psychomotor stimulant drug that has been shown to induce symptoms characteristic of schizophrenia in humans and animals. The aim of these studies was to use the sub-chronic PCP model in rats to investigate cognitive dysfunction in behavioural tests which have been highlighted as relevance by the MATRICS initiative (MATRICS.ucla.edu). The main tests used were attentional set-shifting, operant reversal learning, and novel object recognition tasks. The pharmacology of antipsychotics was studied in the reversal learning task using receptor selective compounds. Following this, experiments were carried out using in vitro electrophysiology and in vivo microdialysis in an attempt to investigate the mechanisms underpinning the PCP-induced cognitive deficits. The attentional set-shifting task is a test of executive function, the extra-dimensional shift (EDS) phase relates to the ability to shift attention to a different stimulus dimension; this is impaired in patients with schizophrenia. The studies presented in chapter 2 showed that sub-chronic PCP administration impaired attentional set-shifting performance selectively in the EDS phase, a deficit which was significantly attenuated by sub-chronic administration of clozapine and risperidone, but not haloperidol. The effect of PCP was also shown to be more robust in female rats compared to males. A deficit in set-shifting ability was also observed in isolation reared rats. However, the deficits produced by PCP were more robust than the deficit produced by isolation rearing. The reversal learning task is another test of executive function. Chapter 3 reported that sub-chronic PCP administration impairs reversal learning ability in an operant task, as demonstrated by reduced percent correct responding in the reversal phase of the reversal learning task. It was found that a D1 agonist (SKF-38398), a 5-HT1A partial agonist (buspirone), a 5-HT2C antagonist (SB-243213A) and an agonist and positive allosteric modulator of the alpha 7 nACh receptor (PNU-282987 and PheTQS respectively) are able to reverse the sub-chronic PCP-induced deficit in reversal learning. Although many antipsychotics have affinity for muscarinic M1 and histamine H1 receptors, selective agents at these receptors were not able to improve the PCP-induced deficit. In chapter 4, the atypical antipsychotics, clozapine and risperidone, when given alone to naïve rats had no effect on reversal learning. Haloperidol when given to naïve rats impaired performance at the highest dose. Sub-chronic PCP was again found to impair reversal learning performance. Investigative experiments revealed that the 2 min time-out could be important as a cue. Following a double reversal, olanzapine-treated rats lost the ability to switch between the rules, whereas clozapine and risperidone-treated rats could perform the double reversal. Experiments with the extended (15 min) reversal phase could allow the investigation of the time-course effects of antipsychotics or selective compounds. The studies presented in chapter 5 found a reduction in gamma oscillations in the CA3 region of the hippocampus, following sub-chronic PCP treatment (2-5 weeks post treatment) that was paralleled by a deficit in parvalbumin immunoreactive (IR) cell density, at a similar time point (2 weeks post treatment). In contrast, a time-dependent increase in gamma oscillations was observed (6-8 weeks post treatment), at which point parvalbumin IR cell density was unchanged (8 weeks post treatment). Gamma oscillations were unchanged in the prefrontal cortex (PFC) following the PCP treatment regime. Locomotor activity tests were also carried out to ensure that the sub-chronic PCP treatment was successful. In-vivo microdialysis revealed that vehicle-treated rats show an increase in dopamine in the PFC which is selective for the retention trial of the novel object recognition task. PCP-treated rats were unable to distinguish between the novel and familiar objects and the increase in dopamine observed in vehicle rats was absent. As a control experiment it was also shown that sub-chronic PCP did not induce anxiety-like symptoms in the elevated plus maze and open field tests. These studies suggest that sub-chronic PCP induces cognitive deficits in behavioural tasks, and these deficits may be due to GABAergic mediated processes in the hippocampus and dopaminergic dysfunction in the PFC. These behavioural and neurochemical results are concurrent to findings observed in schizophrenia.

Phencyclidine (PCP) is a non-competitive NMDA receptor antagonist that has been shown to induce schizophrenia-like psychotic symptoms that are clinically indistinguishable from schizophrenia in patients. When administered to rodents, PCP produces an array of behaviours that are characteristic of schizophrenia. Schizophrenia is associated with continual and treatment resistant cognitive deficits which are now recognised as a core feature of the disease. The aim of the studies reported in chapter 3 were to establish a set of objects with equal preference in the NOR (novel object recognition) test. Furthermore, the inter-trial-interval (ITI) of the NOR test was investigated in an attempt to elucidate the effects of time and location of the rats during the ITI on the cognitive impairments following sub-chronic PCP treatment. The experiments in chapter 4 were designed to compare the performance of male and female rats in the NOR test following treatment with acute d-amphetamine (d-amph), PCP and sub-chronic PCP treatment. In chapter 5, validation of the cognitive deficits induced by sub-chronic PCP treatment was assessed using carefully selected pharmacological agents. The aim of the studies in chapter 6 was to determine the effects of isolation rearing on cognitive performance in the NOR test following increasing ITIs. Additionally, the sensitivity of isolation reared rats compared to social controls following acute administration of PCP and d-amph was assessed using the NOR test. Studies in chapter 8 utilised the 16-holeboard maze to determine the effects of acute treatment with d-amphetamine, PCP and scopolamine on working memory in the rat. NOR is a visual learning and memory test that measures recognition memory which is impaired in patients with schizophrenia. Studies presented in this thesis demonstrate the importance of careful pilot studies when selecting objects for use in the NOR test. Initial studies in sub-chronic PCP (2 mg/kg for 7 days followed by 7 days drug free) treated female hooded-Lister rats revealed a preference of the rats for the wooden cone object; subsequently this object was eliminated from further NOR experiments. Sub-chronic PCP treated rats were found to be highly susceptible to the disruptive influence of distraction during the short 1 min inter-trial-interval (ITI) in the NOR test. These results are consistent with clinical findings of the effects of distraction on cognition in schizophrenia patients. Following the initial validation experiments, a 1 min ITI in the home cage was selected for all subsequent NOR studies. Further experiments provided evidence to confirm that information presented in the acquisition trial is encoded but not retained in the retention trial of the NOR test by IV PCP-treated rats. Male rats were less sensitive to the recognition memory deficits induced by acute treatment with PCP and d-amphetamine compared with females. Following sub-chronic PCP treatment, both males and females showed object recognition deficits, however, the impairments were more robust in female rats. Female rats were therefore selected for all subsequent experiments. Pharmacological validation was carried out using carefully selected agents which were assessed for their ability to restore the sub-chronic PCP induced cognitive deficit in the object recognition test. It was found that the classical antipsychotic agents haloperidol and fluphenazine, the benzodiazepine anxiolytic chlordiazepoxide and the SSRI antidepressant fluoxetine were ineffective. Further studies showed that the atypical antipsychotic agents, clozapine and risperidone, the analeptic agent modafinil, the nAChR full agonist nicotine, and full agonist and positive allosteric modulator of the α7 nAChR (PNU-282987 and PNU120596 respectively) reversed the recognition memory deficit induced by sub-chronic PCP treatment in the NOR test. Isolation rearing of rats at weaning is an environmental stressor that has relevance for modelling the symptomatology and pathology of schizophrenia. Isolates had a significantly increased locomotor activity (LMA) response to a novel environment and enhanced sensitivity to time delay-induced recognition memory deficits, compared with their socially reared counterparts. Isolates were less sensitive to an acute PCP-induced recognition memory deficit but more sensitive to an acute d-amphetamine induced recognition memory deficit in the NOR test compared to social controls. Preliminary results from the 16-holeboard maze experiments reveal that acute administration of the mAChR antagonist scopolamine, d-amphetamine, PCP and sub-chronic PCP treatment reduced working memory scores compared to vehicle treated controls. Taken together, these findings suggest that sub-chronic treatment with PCP induces cognitive deficits in behavioural tests of relevance to cognition associated with schizophrenia. This may allow the detection of novel pharmacotherapies to alleviate these cognitive deficits and exploration of the nature of cognitive disturbances in these patients.

No description available.

A esquizofrenia é uma doença psiquiátrica caracterizada classicamente pela perda de contato com a realidade, onde os pacientes são incapazes de distinguir uma experiência real da imaginária. Pacientes esquizofrênicos apresentam importante transtorno psicossocial e emocional, prejudicando a vida de relações interpessoais e familiares. As características da doença incluem a presença de delírios, alucinações, alterações de comportamento e diminuição da capacidade mental. A etiologia da doença é complexa e multifatorial, estando envolvidos fatores genéticos, biológicos e ambientais. A utilização de medicamentos antipsicóticos é peça fundamental no tratamento. Os fármacos antipsicóticos são agrupados em “típicos” e “atípicos”, atuando sobre o sistema dopaminérgico e serotoninérgico. Neste estudo, foram selecionados 79 pacientes diagnosticados com esquizofrenia, atendidos no Programa de Atendimento do Ambulatório de Esquizofrenia e Demências do Hospital de Clínicas de Porto Alegre, cujo diagnóstico seguiu critérios do CID-10 e DSM-IV. O objetivo do presente estudo foi associar o tempo de exposição de drogas antipsicóticas e o estado nutricional destes pacientes. Para tanto, foram coletados, analisados e interpretados dados referentes a exames laboratoriais, medidas de pressão arterial, avaliação antropométrica e o tempo diagnóstico de início da doença e procura por auxílio clínico. Concluímos que pacientes esquizofrênicos deste estudo apresentam sobrepeso (34,2%), elevada circunferência da cintura (68,4%), elevado índice cintura-quadril (72,2%) e excesso de adiposidade (96,2%) com risco aumentado para alterações metabólicas. Entretanto, apenas o índice cintura-quadril mostrou associação e correlação positiva e significativa com o tempo de uso da medicação. / The schizophrenia is a psychotic illness classically marked by the lost of contact with reality, when the patients are unable to distinguish a real experience from an imaginary one. Schizophrenic patients present an important psychosocial and emotional disorder, affecting the life of interpersonal and family relations. The characteristics of this illness include the presence of delusions, hallucinations, behavior changes and lowering of mental capacity. The etiology of this condition is complex and multifactorial, being involved genetic, biological and environmental factors. The use of antipsychotic drugs is a fundamental part in the process of treatment. The antipsychotic medicines are grouped in typical and atypical, acting on the dopaminergic and serotoninergic systems. This study selected 79 schizofrenic patients who were treated in the Ambulatory Treatment Program for Schizophrenia and Dementia in the Hospital de Clínicas de Porto Alegre, which the diagnoses followed criteria from the CID-10 and DSM-IV. The objective of the present study was to associate the exposition time of antipsychotic drugs and the nutricional condition of these patients. In order to achieve that, rererent data and laboratorial exams, arterial pressure measurement, anthropometric avaluation and the diagnosis time between the beginning of the illness and the search for clinical help were collected, analysed and interpreted. We concluded that the schizophrenic patients in this study present overweight (34,2%), high waist circumference (68,4%), high waist-hip ratio (72,2%) and adipositivity excess (96,2%) with increased risk for metabolic alterations. However, just the waist-hip ratio shown positive and significant association and correlation with the time period of the medication use.

Este trabalho apresenta a continuidade da avaliação farmacológica do derivado Nfenilpiperazínico LASSBio-579 em busca de um novo candidato a antipsicótico de segunda geração. Em estudos anteriores, demonstramos que LASSBio-579 base livre é um potencial candidato a antipsicótico atípico capaz de modular três diferentes sistemas neurotransmissores envolvidos na patofisiologia da esquizofrenia: a neurotransmissão dopaminérgica, serotonérgica e glutamatérgica; entretanto, LASSBio-579 na forma de cloridrato apresenta baixa biodisponibilidade. Neste trabalho avaliamos inicialmente a ação de LASSBio-579.HCl. -ciclodextrina, proposto como alternativa para melhorar a biodisponibilidade. Porém, quando avaliado no modelo de escalada induzida por apomorfina, preditivo de atividade antipsicótica, essa preparação não foi efetiva. Assim, seguimos a avaliação farmacodinâmica com LASSBio-579 base livre, utilizando modelos preditivos de atividade antipsicótica, em camundongos. Neste trabalho foram realizados ainda ensaios in vitro, onde se avaliou a ação de LASSBio-579 sobre a viabilidade celular, captação de glutamato e secreção de proteína S100B, utilizando-se para isso fatias hipocampais de ratos tratadas de forma aguda com LASSBio-579 nas concentrações de 0,1; 1,0; 10 e 20μM. / This study presents the continuity of the pharmacological evaluation of the Nphenilpiperazine derivative LASSBio-579, searching a new second generation antipsychotic compound. In previous studies we have demonstrated that LASSBio- 579 in form of base is a potential atypical antipsychotic able to modulate three different neurotransmitter systems involved in the pathophysiology of schizophrenia: dopaminergic, glutamatergic and serotonergic. However, LASSBio-579 hydrochloride has low bioavailability. In this study we evaluated LASSBio-579.HCl. -cyclodextrin, prepared with the aim of increasing oral bioavailability, in the apomorphine induced climbing in mice, which is a model predictive of antipsychotic activity; and it was not effective. Thus, we continue the study with LASSBio-579 in form of base by testing it in others mice models predictive of antipsychotic activity. In this study, also were made in vitro studies performed in hippocampal acute slices which demonstrated that LASSBio-579 induced a glutamate uptake inhibition and also inhibited the S100B protein secretion.

A esquizofrenia é uma doença psiquiátrica caracterizada classicamente pela perda de contato com a realidade, onde os pacientes são incapazes de distinguir uma experiência real da imaginária. Pacientes esquizofrênicos apresentam importante transtorno psicossocial e emocional, prejudicando a vida de relações interpessoais e familiares. As características da doença incluem a presença de delírios, alucinações, alterações de comportamento e diminuição da capacidade mental. A etiologia da doença é complexa e multifatorial, estando envolvidos fatores genéticos, biológicos e ambientais. A utilização de medicamentos antipsicóticos é peça fundamental no tratamento. Os fármacos antipsicóticos são agrupados em “típicos” e “atípicos”, atuando sobre o sistema dopaminérgico e serotoninérgico. Neste estudo, foram selecionados 79 pacientes diagnosticados com esquizofrenia, atendidos no Programa de Atendimento do Ambulatório de Esquizofrenia e Demências do Hospital de Clínicas de Porto Alegre, cujo diagnóstico seguiu critérios do CID-10 e DSM-IV. O objetivo do presente estudo foi associar o tempo de exposição de drogas antipsicóticas e o estado nutricional destes pacientes. Para tanto, foram coletados, analisados e interpretados dados referentes a exames laboratoriais, medidas de pressão arterial, avaliação antropométrica e o tempo diagnóstico de início da doença e procura por auxílio clínico. Concluímos que pacientes esquizofrênicos deste estudo apresentam sobrepeso (34,2%), elevada circunferência da cintura (68,4%), elevado índice cintura-quadril (72,2%) e excesso de adiposidade (96,2%) com risco aumentado para alterações metabólicas. Entretanto, apenas o índice cintura-quadril mostrou associação e correlação positiva e significativa com o tempo de uso da medicação. / The schizophrenia is a psychotic illness classically marked by the lost of contact with reality, when the patients are unable to distinguish a real experience from an imaginary one. Schizophrenic patients present an important psychosocial and emotional disorder, affecting the life of interpersonal and family relations. The characteristics of this illness include the presence of delusions, hallucinations, behavior changes and lowering of mental capacity. The etiology of this condition is complex and multifactorial, being involved genetic, biological and environmental factors. The use of antipsychotic drugs is a fundamental part in the process of treatment. The antipsychotic medicines are grouped in typical and atypical, acting on the dopaminergic and serotoninergic systems. This study selected 79 schizofrenic patients who were treated in the Ambulatory Treatment Program for Schizophrenia and Dementia in the Hospital de Clínicas de Porto Alegre, which the diagnoses followed criteria from the CID-10 and DSM-IV. The objective of the present study was to associate the exposition time of antipsychotic drugs and the nutricional condition of these patients. In order to achieve that, rererent data and laboratorial exams, arterial pressure measurement, anthropometric avaluation and the diagnosis time between the beginning of the illness and the search for clinical help were collected, analysed and interpreted. We concluded that the schizophrenic patients in this study present overweight (34,2%), high waist circumference (68,4%), high waist-hip ratio (72,2%) and adipositivity excess (96,2%) with increased risk for metabolic alterations. However, just the waist-hip ratio shown positive and significant association and correlation with the time period of the medication use.

Made available in DSpace on 2014-12-17T15:37:14Z (GMT). No. of bitstreams: 1 ValeriaPS_DISSERT (2).pdf: 1441287 bytes, checksum: b2e4b1aca42f441a4c8631f09105903c (MD5) Previous issue date: 2012-04-27 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / T. gondii is an obligate intracellular protozoan and the main cause of retinochoroiditis in humans. The aim of this study was to evaluate the effect of the antipsychotic drugs haloperidol and clozapine on the course of infection by T. gondii of cultured embryonic retinal cells. Embryo retinas of Gallus gallus domesticus (E12) were used for the preparation of mixed monolayer cultures of retinal cells. Cultures were maintained on plates of 96 and 24 wells by 37?C in DMEM medium supplemented with 5% fetal bovine serum for 2 days. After this period, cultures were simultaneously infected with tachyzoites of T. gondii and treated with the antipsychotics haloperidol and clozapine for 48 hours. Treatment effects were determined by both assessing cell viability with the MTT method and evaluating infection outcomes in slides stained with Giemsa. The treatment with haloperidol and clozapine cells infected with T. gondii resulted in higher viability of these cells, suggesting a possible prevention of neuronal degeneration induced by T. gondii. Additionally, intracellular replication of this protozoan in cells treated with haloperidol and clozapine were significantly reduced, possibly by modulation of the parasite s intracellular calcium concentration / T. gondii ? um protozo?rio intracelular obrigat?rio e a principal causa de retinocoroidite em humanos. Este estudo foi conduzido para avalia??o do efeito do tratamento com as drogas antipsic?ticas haloperidol e clozapina sobre a infec??o de T. gondii em cultura de c?lulas retinianas embrion?rias. Retinas de embri?es de Gallus gallus domesticus de doze dias (E12) foram usados para prepara??o de culturas mistas de c?lulas retinianas em monocamada. As culturas foram mantidas em placas de 24 e 96 po?os ? 37?C em meio DMEM suplementado com 5% de soro fetal bovino durante 2 dias. Ap?s este per?odo, as culturas foram simultaneamente infectadas com taquiz?itas de T. gondii e tratadas com os antipsic?ticos haloperidol e clozapina por 48 horas. Os efeitos dos tratamentos das drogas sobre a infec??o deste parasito foram determinados pela avalia??o da viabilidade celular pelo m?todo de MTT e avalia??o de par?metros de infec??o em l?minas coradas pelo m?todo de giemsa. O tratamento com clozapina e haloperidol de c?lulas infectadas com T. gondii resultou em menor preju?zo da viabilidade destas c?lulas, o que sugere uma poss?vel preven??o de degenera??o neuronal induzida por estes antipsic?ticos. Adicionalmente, a replica??o intracelular deste protozo?rio, em c?lulas tratadas com clozapina e haloperidol foi significantemente reduzida, possivelmente pela modula??o da concentra??o intracelular de c?lcio deste parasito

The work deals with a mental illness called schizophrenia. The thesis consists of two parts, the theoretical part and the practical part. The theoretical part has five chapters, it has focused mainly on the interconnectedness of social work, psychiatry, psychology and ethics. First, it describes schizophrenia in general - how begins the illness, it signs and symptoms, diagnosis, course and prognosis and treatment options. I am focusing on the psychiatric aspects of schizophrenia, the social aspect of the disease and the ethics codes of various disciplines. The practical part is research, which is based on the interpretation of the results of a quantitative research. I opted a questionnaire as a research technice. The aim of this questionnaire is to find out which general knowledges has the adult population about schizophrenia and which views of schizophrenia are prevailing.

Este trabalho apresenta a continuidade da avaliação farmacológica do derivado Nfenilpiperazínico LASSBio-579 em busca de um novo candidato a antipsicótico de segunda geração. Em estudos anteriores, demonstramos que LASSBio-579 base livre é um potencial candidato a antipsicótico atípico capaz de modular três diferentes sistemas neurotransmissores envolvidos na patofisiologia da esquizofrenia: a neurotransmissão dopaminérgica, serotonérgica e glutamatérgica; entretanto, LASSBio-579 na forma de cloridrato apresenta baixa biodisponibilidade. Neste trabalho avaliamos inicialmente a ação de LASSBio-579.HCl. -ciclodextrina, proposto como alternativa para melhorar a biodisponibilidade. Porém, quando avaliado no modelo de escalada induzida por apomorfina, preditivo de atividade antipsicótica, essa preparação não foi efetiva. Assim, seguimos a avaliação farmacodinâmica com LASSBio-579 base livre, utilizando modelos preditivos de atividade antipsicótica, em camundongos. Neste trabalho foram realizados ainda ensaios in vitro, onde se avaliou a ação de LASSBio-579 sobre a viabilidade celular, captação de glutamato e secreção de proteína S100B, utilizando-se para isso fatias hipocampais de ratos tratadas de forma aguda com LASSBio-579 nas concentrações de 0,1; 1,0; 10 e 20μM. / This study presents the continuity of the pharmacological evaluation of the Nphenilpiperazine derivative LASSBio-579, searching a new second generation antipsychotic compound. In previous studies we have demonstrated that LASSBio- 579 in form of base is a potential atypical antipsychotic able to modulate three different neurotransmitter systems involved in the pathophysiology of schizophrenia: dopaminergic, glutamatergic and serotonergic. However, LASSBio-579 hydrochloride has low bioavailability. In this study we evaluated LASSBio-579.HCl. -cyclodextrin, prepared with the aim of increasing oral bioavailability, in the apomorphine induced climbing in mice, which is a model predictive of antipsychotic activity; and it was not effective. Thus, we continue the study with LASSBio-579 in form of base by testing it in others mice models predictive of antipsychotic activity. In this study, also were made in vitro studies performed in hippocampal acute slices which demonstrated that LASSBio-579 induced a glutamate uptake inhibition and also inhibited the S100B protein secretion.