In the present study 5-hydroxytryptamine (5-HT) 1A receptor knockout mice (KO), mice overexpressing the 5-HT1A receptor (OE), and wild-type (WT) mice were used to investigate the influence of 5-HT1A receptor on the development of the serotonergic system in the brain, from the embryonic day 12.5 to the postnatal day 15.5. Neither the absence nor the overexpression of 5-HT1A receptor influenced the development and differentiation of serotonergic neurons in the raphe area of the mouse brain. However, a delay in the initial development of the serotonergic projections to the mesencephalic tegmentum, cerebral cortex and hypothalamus was observed in both transgenic mice lines. The brain levels of 5-HT and 5-hydroxyindoleacetic acid were significantly higher in both transgenic mice lines during the late embryonic and early postnatal periods as compared to WT mice. An increase in the turnover of 5-HT was not observed before the early postnatal period. Both the absence and the overexpression of 5-HT1A receptor delayed the development of the dopaminergic system of the mesencephalic tegmentum in the early embryonic period. In OE mice the postnatal development of the noradrenergic system appeared to be exaggerated. The immunoreactivity for the neurotrophic protein S100ß was higher in the cerebral cortex, striatum and hippocampus of OE mice as compare to WT and KO mice. The expression of synaptic proteins, such as synapatobrevin and synaptotagmin was reduced in KO and OE mice during the early embryonic period. This reduction may be linked to the delayed development of the serotonergic projections and the dopaminergic system. In addition, no influence of 5-HT1A receptor mutations on the myelination of the brain was observed. Zusammenfassung In der vorliegenden Arbeit wurden die 5-Hydroxytryptamin (5-HT)1A Rezeptor Knockout (KO), überexprimierenden (ÜE) Mäuse und die Wild-Typ (WT) Mäuse, in den Entwicklungsperioden vom embryonalen Tag 12,5 bis postnatalen Tag 15,5 untersucht, um weitere Informationen über den Einfluss vom 5-HT1A Rezeptor auf die Entwicklung des serotonergen Systems im Gehirn zu erhalten. Sowohl das Fehlen des 5-HT1A Rezeptors als auch dessen Überexpression hatten zwar keinen Einfluss auf die Entwicklung und Differenzierung der serotonergen Neurone in den Raphe Regionen, verzögerte aber die erste Entwicklung der serotonergen Innervierungen im mesencephalen Tegmentum, Hypothalamus und cerebralen Cortex. In den späten embryonalen und insbesondere frühpostnatalen Perioden waren die 5-HT- und 5-HIAA-Spiegel bei KO und ÜE Mäusen im Vergleich zu WT Mäusen signifikant erhöht. Eine Erhöhung des 5-HT Turnovers wurde erst in der frühpostnatalen Periode beobachtet. Auch die Entwicklung des dopaminergen Systems im Mesencephalon war in der frühen embryonalen Periode sowohl bei KO als auch bei ÜE Mäusen verlangsamt. Die Überexpression des 5-HT1A Rezeptors begünstigte möglicherweise die postnatale Entwicklung des noradrenergen Systems. Bei ÜE Mäusen war die Immunreaktivität des neurotrophen Proteins S100? im cerebralen Cortex, Hippocampus und Striatum stärker als bei WT und KO Mäusen. Die Expression der synaptischen Proteine wie Synaptobrevin und Synaptotagmin war sowohl bei KO als auch bei ÜE Mäusen in der frühen embryonalen Periode verzögert. Dies könnte mit der verzögerten Entwicklung der serotonergen Projektionen und des dopaminergen Systems in Zusammenhang stehen. Darüber hinaus hatten transgene Veränderungen am 5-HT1A Rezeptor keinen Einfluss auf die Myelinisierung im Gehirn der Maus. Schlagwörter: serotonerges System, Entwicklung des Gehirns, 5-HT1A Rezeptor, transgene Mäuse, dopaminerges System, noradrenerges System, S100ß, Synaptisches Protein, Myelinisierung / In the present study 5-hydroxytryptamine (5-HT) 1A receptor knockout mice (KO), mice overexpressing the 5-HT1A receptor (OE), and wild-type (WT) mice were used to investigate the influence of 5-HT1A receptor on the development of the serotonergic system in the brain, from the embryonic day 12.5 to the postnatal day 15.5. Neither the absence nor the overexpression of 5-HT1A receptor influenced the development and differentiation of serotonergic neurons in the raphe area of the mouse brain. However, a delay in the initial development of the serotonergic projections to the mesencephalic tegmentum, cerebral cortex and hypothalamus was observed in both transgenic mice lines. The brain levels of 5-HT and 5-hydroxyindoleacetic acid were significantly higher in both transgenic mice lines during the late embryonic and early postnatal periods as compared to WT mice. An increase in the turnover of 5-HT was not observed before the early postnatal period. Both the absence and the overexpression of 5-HT1A receptor delayed the development of the dopaminergic system of the mesencephalic tegmentum in the early embryonic period. In OE mice the postnatal development of the noradrenergic system appeared to be exaggerated. The immunoreactivity for the neurotrophic protein S100ß was higher in the cerebral cortex, striatum and hippocampus of OE mice as compare to WT and KO mice. The expression of synaptic proteins, such as synapatobrevin and synaptotagmin was reduced in KO and OE mice during the early embryonic period. This reduction may be linked to the delayed development of the serotonergic projections and the dopaminergic system. In addition, no influence of 5-HT1A receptor mutations on the myelination of the brain was observed.

Fundamentação: O acidente vascular cerebral (AVC) é uma das principais causas de morte em todo o mundo e a maioria dos sobreviventes permanece com alguma sequela neurológica após o evento agudo. O presente estudo objetiva investigar a associação de alguns biomarcadores sanguíneos com as escalas de AVC, bem como avaliar a capacidade dos biomarcadores selecionados na predição de desfechos neurológicos durante o tempo de acompanhamento. Material e Métodos: Incluímos nesse estudo 60 pacientes com AVC agudo admitidos na unidade neurovascular da emergência ou na unidade de medicina intensiva do Hospital de Clínicas de Porto Alegre, nas primeiras 24 horas do início dos sintomas. Foram coletas amostras sanguíneas nas primeiras 24 horas, no terceiro e no quinto dias após o AVC para dosagem de enolase neurônio específica (ENS), proteína S100ß (S100ß), interleucina 6 (IL-6), proteína C reativa (PCR) e fator neurotrófico derivado do cérebro (BDNF). A gravidade do AVC e o grau de dependência funcional dos pacientes após o AVC foram mensurados através das escalas do National Institutes of Health Stroke Scale (NIHSS) e modified Rankin Scale (mRS) nos três momentos das coletas sanguíneas e na alta hospitalar. Resultados: Os níveis séricos de S100ß, IL-6 e PCR mostraram-se o melhor painel de biomarcadores após o AVC nesse estudo. Quando os pacientes foram subdivididos em dois grupos para a avaliação de desfechos neurológicos, usando as escalas do NIHSS (NIHSS ≤ 6 e NHISS > 6) e mRS (mRS ≤ 3 e mRS > 3), ambas as escalas apresentaram boa associação entre as concentrações de S100ß e de IL-6 em todas as medidas e as escalas de AVC para bom prognóstico (NIHSS ≤ 6 e mRS ≤ 3) na alta hospitalar. Dentre os biomarcadores selecionados para o estudo, foram os três citados acima que apresentaram as melhores correlações com as escalas de AVC e com o prognóstico pós AVC durante o tempo de acompanhamento. Conclusão: Os biomarcadores séricos podem ser úteis na avaliação da gravidade e do prognóstico após o AVC. A associação de S100ß, IL-6 e PCR parece acrescentar pouco às escalas validadas de AVC na capacidade de predizer desfechos após o evento agudo. / Background and Purpose: Stroke is an important cause of death worldwide, and the majority of stroke survivors suffer from some form of residual disability. This study aimed to investigate the association of blood biomarkers with stroke scales and their predictive value after acute stroke at the time of admission until hospital discharge. Design and Methods: We investigated 60 patients with acute stroke who were admitted within 24 h of event onset at the intensive care unit or neurovascular emergency unit of Clínicas Hospital. All patients provided venous blood samples for the measurement of neuron-specific enolase (NSE), S100ß protein (S100ß), interleukin-6 (IL-6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) within 24 h of the acute event, on the third day and on the fifth day after the stroke. Neurological stroke severity and global disability were determined with the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at the same three times of blood collection and at the time of hospital discharge. Results: The serum levels of the S100ß protein, IL-6 and CRP seem to constitute the best panel of biomarkers after acute stroke in this study. When patients were subdivided into two groups according to the NIHSS (NIHSS ≤ 6 and NIHSS > 6) and mRS (mRS ≤ 3 and mRS > 3) scores, which were used as neurological outcome measures, both neurologic scores for good outcome (NIHSS ≤ 6 and mRS ≤ 3) at hospital discharge were significantly related to the S100ß protein and IL-6 levels at all of the measured time points. Among the analyzed blood markers, S100ß, IL-6 and PCR levels significanttly correlated with the stroke scales and prognostic value. Conclusion: Blood biomarkers may be useful in acute stroke either by suggesting stroke severity or providing a prognostic value. The addition of the S100ß protein, IL-6 and CRP to previously validated stroke scales slightly improves the ability of these scales to predict outcome.

Fundamentação: O acidente vascular cerebral (AVC) é uma das principais causas de morte em todo o mundo e a maioria dos sobreviventes permanece com alguma sequela neurológica após o evento agudo. O presente estudo objetiva investigar a associação de alguns biomarcadores sanguíneos com as escalas de AVC, bem como avaliar a capacidade dos biomarcadores selecionados na predição de desfechos neurológicos durante o tempo de acompanhamento. Material e Métodos: Incluímos nesse estudo 60 pacientes com AVC agudo admitidos na unidade neurovascular da emergência ou na unidade de medicina intensiva do Hospital de Clínicas de Porto Alegre, nas primeiras 24 horas do início dos sintomas. Foram coletas amostras sanguíneas nas primeiras 24 horas, no terceiro e no quinto dias após o AVC para dosagem de enolase neurônio específica (ENS), proteína S100ß (S100ß), interleucina 6 (IL-6), proteína C reativa (PCR) e fator neurotrófico derivado do cérebro (BDNF). A gravidade do AVC e o grau de dependência funcional dos pacientes após o AVC foram mensurados através das escalas do National Institutes of Health Stroke Scale (NIHSS) e modified Rankin Scale (mRS) nos três momentos das coletas sanguíneas e na alta hospitalar. Resultados: Os níveis séricos de S100ß, IL-6 e PCR mostraram-se o melhor painel de biomarcadores após o AVC nesse estudo. Quando os pacientes foram subdivididos em dois grupos para a avaliação de desfechos neurológicos, usando as escalas do NIHSS (NIHSS ≤ 6 e NHISS > 6) e mRS (mRS ≤ 3 e mRS > 3), ambas as escalas apresentaram boa associação entre as concentrações de S100ß e de IL-6 em todas as medidas e as escalas de AVC para bom prognóstico (NIHSS ≤ 6 e mRS ≤ 3) na alta hospitalar. Dentre os biomarcadores selecionados para o estudo, foram os três citados acima que apresentaram as melhores correlações com as escalas de AVC e com o prognóstico pós AVC durante o tempo de acompanhamento. Conclusão: Os biomarcadores séricos podem ser úteis na avaliação da gravidade e do prognóstico após o AVC. A associação de S100ß, IL-6 e PCR parece acrescentar pouco às escalas validadas de AVC na capacidade de predizer desfechos após o evento agudo. / Background and Purpose: Stroke is an important cause of death worldwide, and the majority of stroke survivors suffer from some form of residual disability. This study aimed to investigate the association of blood biomarkers with stroke scales and their predictive value after acute stroke at the time of admission until hospital discharge. Design and Methods: We investigated 60 patients with acute stroke who were admitted within 24 h of event onset at the intensive care unit or neurovascular emergency unit of Clínicas Hospital. All patients provided venous blood samples for the measurement of neuron-specific enolase (NSE), S100ß protein (S100ß), interleukin-6 (IL-6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) within 24 h of the acute event, on the third day and on the fifth day after the stroke. Neurological stroke severity and global disability were determined with the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at the same three times of blood collection and at the time of hospital discharge. Results: The serum levels of the S100ß protein, IL-6 and CRP seem to constitute the best panel of biomarkers after acute stroke in this study. When patients were subdivided into two groups according to the NIHSS (NIHSS ≤ 6 and NIHSS > 6) and mRS (mRS ≤ 3 and mRS > 3) scores, which were used as neurological outcome measures, both neurologic scores for good outcome (NIHSS ≤ 6 and mRS ≤ 3) at hospital discharge were significantly related to the S100ß protein and IL-6 levels at all of the measured time points. Among the analyzed blood markers, S100ß, IL-6 and PCR levels significanttly correlated with the stroke scales and prognostic value. Conclusion: Blood biomarkers may be useful in acute stroke either by suggesting stroke severity or providing a prognostic value. The addition of the S100ß protein, IL-6 and CRP to previously validated stroke scales slightly improves the ability of these scales to predict outcome.

Fundamentação: O acidente vascular cerebral (AVC) é uma das principais causas de morte em todo o mundo e a maioria dos sobreviventes permanece com alguma sequela neurológica após o evento agudo. O presente estudo objetiva investigar a associação de alguns biomarcadores sanguíneos com as escalas de AVC, bem como avaliar a capacidade dos biomarcadores selecionados na predição de desfechos neurológicos durante o tempo de acompanhamento. Material e Métodos: Incluímos nesse estudo 60 pacientes com AVC agudo admitidos na unidade neurovascular da emergência ou na unidade de medicina intensiva do Hospital de Clínicas de Porto Alegre, nas primeiras 24 horas do início dos sintomas. Foram coletas amostras sanguíneas nas primeiras 24 horas, no terceiro e no quinto dias após o AVC para dosagem de enolase neurônio específica (ENS), proteína S100ß (S100ß), interleucina 6 (IL-6), proteína C reativa (PCR) e fator neurotrófico derivado do cérebro (BDNF). A gravidade do AVC e o grau de dependência funcional dos pacientes após o AVC foram mensurados através das escalas do National Institutes of Health Stroke Scale (NIHSS) e modified Rankin Scale (mRS) nos três momentos das coletas sanguíneas e na alta hospitalar. Resultados: Os níveis séricos de S100ß, IL-6 e PCR mostraram-se o melhor painel de biomarcadores após o AVC nesse estudo. Quando os pacientes foram subdivididos em dois grupos para a avaliação de desfechos neurológicos, usando as escalas do NIHSS (NIHSS ≤ 6 e NHISS > 6) e mRS (mRS ≤ 3 e mRS > 3), ambas as escalas apresentaram boa associação entre as concentrações de S100ß e de IL-6 em todas as medidas e as escalas de AVC para bom prognóstico (NIHSS ≤ 6 e mRS ≤ 3) na alta hospitalar. Dentre os biomarcadores selecionados para o estudo, foram os três citados acima que apresentaram as melhores correlações com as escalas de AVC e com o prognóstico pós AVC durante o tempo de acompanhamento. Conclusão: Os biomarcadores séricos podem ser úteis na avaliação da gravidade e do prognóstico após o AVC. A associação de S100ß, IL-6 e PCR parece acrescentar pouco às escalas validadas de AVC na capacidade de predizer desfechos após o evento agudo. / Background and Purpose: Stroke is an important cause of death worldwide, and the majority of stroke survivors suffer from some form of residual disability. This study aimed to investigate the association of blood biomarkers with stroke scales and their predictive value after acute stroke at the time of admission until hospital discharge. Design and Methods: We investigated 60 patients with acute stroke who were admitted within 24 h of event onset at the intensive care unit or neurovascular emergency unit of Clínicas Hospital. All patients provided venous blood samples for the measurement of neuron-specific enolase (NSE), S100ß protein (S100ß), interleukin-6 (IL-6), C-reactive protein (CRP) and brain-derived neurotrophic factor (BDNF) within 24 h of the acute event, on the third day and on the fifth day after the stroke. Neurological stroke severity and global disability were determined with the National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) at the same three times of blood collection and at the time of hospital discharge. Results: The serum levels of the S100ß protein, IL-6 and CRP seem to constitute the best panel of biomarkers after acute stroke in this study. When patients were subdivided into two groups according to the NIHSS (NIHSS ≤ 6 and NIHSS > 6) and mRS (mRS ≤ 3 and mRS > 3) scores, which were used as neurological outcome measures, both neurologic scores for good outcome (NIHSS ≤ 6 and mRS ≤ 3) at hospital discharge were significantly related to the S100ß protein and IL-6 levels at all of the measured time points. Among the analyzed blood markers, S100ß, IL-6 and PCR levels significanttly correlated with the stroke scales and prognostic value. Conclusion: Blood biomarkers may be useful in acute stroke either by suggesting stroke severity or providing a prognostic value. The addition of the S100ß protein, IL-6 and CRP to previously validated stroke scales slightly improves the ability of these scales to predict outcome.