ABSTRACT
MDMA, an addictive psychostimulant-consumed worldwide, has the ability to induce neurotoxic effects and addiction in laboratory animals and in humans through its effects on monoaminergic systems. MDMA-induced neurotoxicity in mice occurs primarily in dopaminergic neurons and does not significantly affect the serotonergic system. As the neurotoxic effects of MDMA in mice involve excessive dopamine (DA) release, DA receptors are highly likely to play a role in MDMA neurotoxicity, but the specific dopamine receptor subtypes involved have not previously been determined definitively. In this study, dopamine D1 and D4 receptor knock-out mice (D1R(-/-) and D4R(-/-)) were used to determine whether these receptors are involved in MDMA neurotoxicity. D1R inactivation attenuated MDMA-induced hyperthermia, decreased the reduction of dopamine and dopamine metabolite levels, and protected against dopamine terminal loss and reactive astrogliosis as determined in the striatum, 7 days after MDMA treatment. In sharp contrast, inactivation of D4R did not prevent hyperthermia or the neurotoxic effects of MDMA. Altogether, these results indicate that D1R, but not D4R, plays a significant role in the dopaminergic striatal neurotoxicity observed after exposure to MDMA.
Subject(s)
Corpus Striatum/drug effects , N-Methyl-3,4-methylenedioxyamphetamine/toxicity , Psychotropic Drugs/toxicity , Receptors, Dopamine D1/genetics , Receptors, Dopamine D4/genetics , Animals , Corpus Striatum/metabolism , Dopamine/metabolism , Female , Fever/chemically induced , Fever/metabolism , Male , Mice , Mice, KnockoutABSTRACT
Methamphetamine is a synthetic drug consumed by millions of users despite its neurotoxic effects in the brain, leading to loss of dopaminergic fibres and cell bodies. Moreover, clinical reports suggest that methamphetamine abusers are predisposed to Parkinson's disease. Therefore, it is important to elucidate the mechanisms involved in methamphetamine-induced neurotoxicity. Dopamine receptors may be a plausible target to prevent this neurotoxicity. Genetic inactivation of dopamine D1 or D2 receptors protects against the loss of dopaminergic fibres in the striatum and loss of dopaminergic neurons in the substantia nigra. Protection by D1 receptor inactivation is due to blockade of hypothermia, reduced dopamine content and turnover and increased stored vesicular dopamine in D1R(-/-) mice. However, the neuroprotective impact of D2 receptor inactivation is partially dependent on an effect on body temperature, as well as on the blockade of dopamine reuptake by decreased dopamine transporter activity, which results in reduced intracytosolic dopamine levels in D2R(-/-) mice.
Subject(s)
Dopamine Agents/toxicity , Methamphetamine/toxicity , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/metabolism , Receptors, Dopamine/drug effects , Animals , Humans , Mice , Oxidative Stress/drug effects , Receptors, Dopamine/metabolism , Receptors, Dopamine D1/drug effects , Receptors, Dopamine D2/drug effectsABSTRACT
Methamphetamine (METH) is a potent, highly addictive psychostimulant consumed worldwide. In humans and experimental animals, repeated exposure to this drug induces persistent neurodegenerative changes. Damage occurs primarily to dopaminergic neurons, accompanied by gliosis. The toxic effects of METH involve excessive dopamine (DA) release, thus DA receptors are highly likely to play a role in this process. To define the role of D(1) receptors in the neurotoxic effects of METH we used D(1) receptor knock-out mice (D(1)R(-/-)) and their WT littermates. Inactivation of D(1)R prevented METH-induced dopamine fibre loss and hyperthermia, and increases in gliosis and pro-inflammatory molecules such as iNOS in the striatum. In addition, D(1)R inactivation prevented METH-induced loss of dopaminergic neurons in the substantia nigra. To explore the relationship between hyperthermia and neurotoxicity, METH was given at high ambient temperature (29 °C). In this condition, D(1)R(-/-) mice developed hyperthermia following drug delivery and the neuroprotection provided by D(1)R inactivation at 23 °C was no longer observed. However, reserpine, which empties vesicular dopamine stores, blocked hyperthermia and strongly potentiated dopamine toxicity in D(1)R(-/-) mice, suggesting that the protection afforded by D(1)R inactivation is due to both hypothermia and higher stored vesicular dopamine. Moreover, electrical stimulation evoked higher DA overflow in D(1)R(-/-) mice as demonstrated by fast scan cyclic voltammetry despite their lower basal DA content, suggesting higher vesicular DA content in D(1)R(-/-) than in WT mice. Altogether, these results indicate that the D(1)R plays a significant role in METH-induced neurotoxicity by mediating drug-induced hyperthermia and increasing the releasable cytosolic DA pool.
Subject(s)
Brain/drug effects , Brain/pathology , Central Nervous System Stimulants/toxicity , Methamphetamine/toxicity , Receptors, Dopamine D1/metabolism , Animals , Brain/metabolism , Dopamine/metabolism , Female , Fever/genetics , Fever/metabolism , Immunohistochemistry , Male , Mice , Mice, Knockout , Receptors, Dopamine D1/geneticsABSTRACT
Pleiotrophin (PTN) is a neurotrophic factor with important effects in survival and differentiation of dopaminergic neurons that has been suggested to play important roles in drug of abuse-induced neurotoxicity. To test this hypothesis, we have studied the effects of amphetamine (10 mg/kg, four times, every 2 h) on the nigrostriatal pathway of PTN genetically deficient (PTN-/-) mice. We found that amphetamine causes a significantly enhanced loss of dopaminergic terminals in the striatum of PTN-/- mice compared to wild type (WT+/+) mice. In addition, we found a significant decrease ( approximately 20%) of tyrosine hydroxylase (TH)-positive neurons only in the substantia nigra of amphetamine-treated PTN-/- mice, whereas this area of WT+/+ animals remained unaffected after amphetamine treatment. This effect was accompanied by enhanced amphetamine-induced astrocytosis in the substantia nigra of PTN-/- mice. Interestingly, we found a significant decrease in the phosphorylation levels of p42 extracellular-signal regulated kinase (ERK2) in both saline- and amphetamine-treated PTN-/- mice, whereas phosphorylation of p44 ERK (ERK1) was almost abolished in the striatum of PTN-/- mice compared to WT+/+ mice, suggesting that basal deficiencies in the phosphorylation levels of ERK1/2 could underlie the higher vulnerability of PTN-/- mice to amphetamine-induced neurotoxic effects. The data suggest an important role of PTN in the protection of nigrostriatal pathways against amphetamine insult.
Subject(s)
Amphetamine/toxicity , Carrier Proteins/genetics , Corpus Striatum/physiology , Cytokines/deficiency , Cytokines/genetics , Gene Silencing/physiology , Substantia Nigra/physiology , Animals , Cell Count/methods , Corpus Striatum/drug effects , Corpus Striatum/pathology , Gene Silencing/drug effects , Male , Mice , Mice, Knockout , Substantia Nigra/drug effects , Substantia Nigra/pathologyABSTRACT
Com objetivo de estimar a sensibilidade, especificidade, valores preditivos e a concordância do Sistema de Informações sobre Mortalidade (SIM), em comparação à investigação de morte materna, foram analisados todos os óbitos de mulheres de 10 a 49 anos de idade ocorridos em 2004 e registrados no SIM como residentes no Município de Belém, capital do Estado do Pará, Brasil. O resultado da investigação revelou uma sensibilidade de 75% do SIM na detecção dos óbitos maternos. Na impossibilidade de investigar todos os óbitos de mulheres em idade reprodutiva, a investigação dos óbitos classificados como presumíveis e declarados, segundo os critérios de definições empregados no estudo, foi suficiente para identificar os demais óbitos maternos. Os campos 43 e 44 da declaração de óbito (DO) apresentaram-se bem preenchidos, com 91% de concordância com a pesquisa. O estudo confirma a necessidade da investigação de tais óbitos para melhorar a qualidade das informações sobre a mortalidade materna.
With the aim to estimate the sensibility, specificity, predictive values and Mortality Information System (SIM) agreement, in matching to the investigation of maternal death, all the deaths of women aged 10 through 49 years, recorded in 2004 in the SIM as residents in the Municipality of Belém, capital of the State of Pará, Brazil, were investigated. The research revealed a 75% of SIM sensitivity regarding detection of those maternal deaths, and that, being impossible to investigate all the deaths of women in childbearing age, the investigation of those deaths classified as presumable and declared, according to the criteria and definitions used in the study, was sufficient to identify all the maternal deaths. Fields 43 and 44 of the death certificate (DO) were well filled out, revealing 91% of concordance to the investigation. This study confirms the need to investigate those deaths aiming to improve the quality of the information on maternal mortality.
Subject(s)
Humans , Female , Pregnancy , Cause of Death , Mortality/statistics & numerical data , Health Status Indicators , Maternal MortalityABSTRACT
Com o objetivo de conhecer a magnitude da mortalidade em Belém, Estado do Para, no ano de 2004, foram investigados todos os óbitos de mulheres em idade reprodutiva residentes no Município, o que possibilitou uma análise da qualidade do Sistema de Informações sobre Mortalidade (SIM) no tocante ao evento estudado. Os resultados revelaram elevado percentual de óbitos evitáveis (76,6 por cento), com predominância das causas obstétricas diretas (92,8 por cento). Encontrou-se 50 por cento de subnumeração de óbito materno no SIM e uma razão de mortalidade materna de 43,0/100.000 nascidos vivos a qual foi inferior à razão obtida por meio de o SIM ter registrado óbitos maternos não confirmados pelo estudo. Concluiu-se que tão-somente a investigação desses óbitos e o acompanhamento do processo de trabalho do SIM são capazes de qualificar as informações e subsidiar adequadamente a elaboração de políticas de saúde que visem à redução da mortalidade materna..
The main objective of this paper was to know the importance of maternal deaths in 2004 in the city of Belém, capital of the State of Pará. All the cases of deaths involving women living in Belém-PA who were in their reproductive age were investigated and as a result it become possible to analyze the quality of the Mortality Information System (SIM) used in the analysis concerning the events being studied. The outcomes of the analysis revealed a high percentage of avoidable deaths (78.6%), in which most of the cases were related to direct obstetric causes (92.8%). The maternal mortality ratio was 45.0/100,000 new born, with a 50% reduction in the records of maternal death in the SIM, in which occurred a correction factor of 0.85. This difference can be explained due to the fact that SIM had registered non-confirmed maternal deaths in the study. It was possible to conclude that only the investigation of these death cases and the follow up of the SIM's work are able to qualify the information and provide proper basis to create new heath policies aiming at the reduction of maternal death.
Subject(s)
Humans , Female , Cause of Death , Information Systems , Maternal Mortality , MortalityABSTRACT
Starting with a spontaneous B-A centric fusion found in a natural population of the grasshopper Eyprepocnemis plorans, we have obtained different strains carrying the rearrangement in various conditions and doses. Using this material, we have analyzed the meiotic behavior of the translocated chromosome in living cultured spermatocytes, simulating the successive steps of a hypothetical process of integration of a B chromosome into the standard genome via B-A centric fusion. Remarkably, the behavior of fusion heterozygotes, the initial step of the integration process, is much more regular than that of any other configuration, including homozygotes. The reasons for the failure of B chromosome integration into the normal complement by translocation are discussed.
Subject(s)
Chromosomes/genetics , Animals , Chromosome Segregation/genetics , Grasshoppers/cytology , Grasshoppers/genetics , Heterozygote , Homozygote , Male , Meiosis/genetics , Translocation, Genetic/genetics , X Chromosome/geneticsABSTRACT
A doença meningocócica (DM) continua merecendo avaliaçöes quanto a sua multicausalidade endêmica e epidêmica e seu comportamento evolutivo, nos diferentes locais. Partindo da padronizaçäo da investigaçäo epidemiológica da DM no Município do Rio de Janeiro a partir da epidemia da década de 70, foram analisados 4.155 casos notificados de 1976 a 1994, através de estudo retrospectivo, descritivo e analítico, com base nas fichas de investigaçäo epidemiológica da Secretaria Municipal de Saúde. Os testes utilizados para análise estatística foram: o X2, o de Wilcoxon-Mann-Whitney e de Kruskal-Wallis. O estudo resultou na definiçäo de três períodos, classificados como pós-epidêmico (1976/79), endêmico (1980/86) e epidêmico (1987/94), diferenciados pelas taxas de incidência e pelo sorogrupo do meningococo predominante. As taxas de incidência médias por período no município foram, respectivamente, de 3,51; 1,67 e 6,53 casos/100.000 habitantes. Os sorogrupos A e C predominaram no período pós-epidêmico, o B e o A no endêmico e o B no epidêmico. A letalidade média praticamente näo se modificou no decorrer do tempo, mas variou segundo o hospital de internaçäo, tendo sido sempre menor no hospital estadual de referência em relaçäo aos demais públicos e privados. As maiores taxas de incidência e letalidade corresponderam aos menores de um ano e o risco de adoecer foi maior no sexo masculino. Os maiores coeficientes de incidência tenderam a ocorrer nas mesmas áreas do município, nos três períodos epidemiológicos, e a populaçäo que reside em favelas teve um risco de adoecimento duas vezes maior
Subject(s)
Infant , Child, Preschool , Child , Adolescent , Adult , Middle Aged , Humans , Male , Female , Meningococcal Infections/epidemiology , Sex Factors , Incidence , Hospitals, Private , Health Services Accessibility , Residence Characteristics , Age Factors , Hospitals, Public , Meningococcal Infections/mortality , Disease Notification , Quality of Health CareABSTRACT
Macacos Cebus apella sp foram infectados com cepas de Trypanosoma cruzi (Y e Sao Felipe), e submetidos, na fase cronica da doenca (1 a 5 anos de infeccao), a xenodiagnosticos e testes sorologicos (aglutinacao direta), revelando porcentuais elevados de positividade. Ao mesmo tempo, outros macacos, nao infectados, foram tambem submetidos aos mesmos testes, cujos resultados foram negativos. Dois dos macacos infectados foram tratados com compostos ativos, previamente testados em camundongos e cujos resultados parasitologicos em primatas foram concordantes com as atividades, total e parcial, dos compostos estudados. Os Autores discutem o emprego do xenodiagnostico e de testes sorologicos como metodos de avaliacao de infeccao e de controle apos a terapeutica e sugerem o macaco como um provavel modelo para estudos de quimioterapicos na fase cronica da doenca de Chagas
