RESUMO
Parkinson's disease is the most common movement disorder, affecting about 1% of the population over the age of 60 years. Parkinson's disease is characterized clinically by resting tremor, bradykinesia, rigidity and postural instability, as a result of the progressive loss of nigrostriatal dopaminergic neurons. In addition to this neuronal cell loss, Parkinson's disease is characterized by the accumulation of intracellular protein aggregates, Lewy bodies and Lewy neurites, composed primarily of the protein α-synuclein. Although it was first described almost 200 years ago, there are no disease-modifying drugs to treat patients with Parkinson's disease. In addition to conventional therapies, non-pharmacological treatment strategies are under investigation in patients and animal models of neurodegenerative disorders. Among such strategies, environmental enrichment, comprising physical exercise, cognitive stimulus, and social interactions, has been assessed in preclinical models of Parkinson's disease. Environmental enrichment can cause structural and functional changes in the brain and promote neurogenesis and dendritic growth by modifying gene expression, enhancing the expression of neurotrophic factors and modulating neurotransmission. In this review article, we focus on the current knowledge about the molecular mechanisms underlying environmental enrichment neuroprotection in Parkinson's disease, highlighting its influence on the dopaminergic, cholinergic, glutamatergic and GABAergic systems, as well as the involvement of neurotrophic factors. We describe experimental pre-clinical data showing how environmental enrichment can act as a modulator in a neurochemical and behavioral context in different animal models of Parkinson's disease, highlighting the potential of environmental enrichment as an additional strategy in the management and prevention of this complex disease.
RESUMO
Huntington's disease (HD) is a genetic disorder marked by transcriptional alterations that result in neuronal impairment and death. MicroRNAs (miRNAs) are non-coding RNAs involved in post-transcriptional regulation and fine-tuning of gene expression. Several studies identified altered miRNA expression in HD and other neurodegenerative diseases, however their roles in early stages of HD remain elusive. Here, we deep-sequenced miRNAs from the striatum of the HD mouse model, BACHD, at the age of 2 and 8 months, representing the pre-symptomatic and symptomatic stages of the disease. Our results show that 44 and 26 miRNAs were differentially expressed in 2- and 8-month-old BACHD mice, respectively, as compared to wild-type controls. Over-representation analysis suggested that miRNAs up-regulated in 2-month-old mice control the expression of genes crucial for PI3K-Akt and mTOR cell signaling pathways. Conversely, miRNAs regulating genes involved in neuronal disorders were down-regulated in 2-month-old BACHD mice. Interestingly, primary striatal neurons treated with anti-miRs targeting two up-regulated miRNAs, miR-449c-5p and miR-146b-5p, showed higher levels of cell death. Therefore, our results suggest that the miRNAs altered in 2-month-old BACHD mice regulate genes involved in the promotion of cell survival. Notably, over-representation suggested that targets of differentially expressed miRNAs at the age of 8 months were not significantly enriched for the same pathways. Together, our data shed light on the role of miRNAs in the initial stages of HD, suggesting a neuroprotective role as an attempt to maintain or reestablish cellular homeostasis.
Assuntos
Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doença de Huntington/genética , MicroRNAs/biossíntese , MicroRNAs/genética , Neuroproteção/fisiologia , Sintomas Prodrômicos , Animais , Células Cultivadas , Feminino , Doença de Huntington/metabolismo , Doença de Huntington/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Análise de Sequência de RNA/métodos , Regulação para Cima/fisiologiaRESUMO
Stroke is considered one of the leading causes of death worldwide. The treatment is limited; however, the Brazilian flora has a great source of natural products with therapeutic potentials. Studies with the medicinal plant Polygala sabulosa W. Bennett provided evidence for its use as an anti-inflammatory and neuroprotective drug. In the case of ischemic stroke due to lack of oxygen, both acute and chronic inflammatory processes are activated. Thus, we hypothesized that P. sabulosa (HEPs) has the potential to treat the motor and cognitive deficits generated by ischemic stroke. Male mice were subjected to global ischemia for 60 min, followed by reperfusion and orally treated with HEPs (100 mg/kg in saline + 3% tween 20) twice a day (12 h apart) for 48 h starting 3 h after surgery. Motor skills were assessed using grip force and open field tasks. Hippocampi were then collected for mRNA quantification of the cytokines IL-1-ß and TNF-α levels. After 48 h of acute treatment, spatial reference memory was evaluated in a Morris water maze test for another group of animals. We show that HEPs treatment significantly prevented motor weakness induced by ischemia. Brain infarct area was reduced by 22.25% with downregulation of the levels of IL-1ß and TNF-α mRNA. Learning performance and memory ability on Morris water maze task were similar to the sham group. Our data demonstrates the neuroprotective properties of HEPs through its anti-inflammatory activities, which prevent motor and cognitive impairments, suggesting that HEPs may be an effective therapy for ischemic stroke.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Transtornos Motores/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Polygala , Animais , Isquemia Encefálica/metabolismo , Cognição/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Força da Mão , Interleucina-1beta/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Transtornos Motores/metabolismo , Destreza Motora/efeitos dos fármacos , Força Muscular/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG nucleotide expansion, which encodes the amino acid glutamine, in the huntingtin gene. HD is characterized by motor, cognitive, and psychiatric dysfunctions. In a previous study, we showed by qPCR that some genes altered in an HD mouse model were also altered in blood of HD patients. These alterations were mainly with respect to the dynein family. Therefore, this study aimed to investigate whether dynein light chain Tctex type 1 (DYNLT1) is altered in HD patients and if there is a correlation between DYNLT1 gene expression changes and disease progression. We assessed the DYNLT1 gene expression in the blood of 19 HD patients and 20 healthy age-matched controls. Also, in 6 of these patients, we analyzed the DYNLT1 expression at two time points, 3 years apart. The DYNLT1 gene expression in the whole blood of HD patients was significantly downregulated and this difference was widened in later stages. These data suggest that DYNLT1 could emerge as a peripheral prognostic indicator in HD and, also, might be a target for potential intervention in the future.
Assuntos
Dineínas/genética , Doença de Huntington , Animais , Estudos de Casos e Controles , Modelos Animais de Doenças , Progressão da Doença , Dineínas/sangue , Expressão Gênica , Humanos , Proteína Huntingtina/genética , Doença de Huntington/genética , CamundongosRESUMO
Acute organophosphate (OP) poisoning induces well-known signs of toxicosis related to acetylcholinesterase (AChE) inhibition. However, the relationship between acute OP poisoning and the onset of psychiatric disorders remains unclear. Thus, we investigated behavioural and biochemical consequences of acute exposure to the OP chlorpyrifos in male rats and also the effectiveness of the antidotes atropine and pralidoxime on reversing these changes. A sub-lethal dose of commercial chlorpyrifos (20â¯mg/kg, i.p.) elicited signs of acute toxicosis during the first hours after its injection in rats. Twenty-four hours after treatment, this single dose of chlorpyrifos induced a depressive-like behaviour in the rat forced swimming test without impairing locomotor activity. At this time (24â¯h), chlorpyrifos decreased plasma butyrylcholinesterase (BChE) activity and hippocampal, striatal and prefrontal cortical AChE activity in rats. The behavioural and biochemical consequences of acute chlorpyrifos poisoning do not seem to be long lasting, since 30â¯days later they were absent. We evaluated whether these behavioural and biochemical consequences of acute chlorpyrifos treatment would be reversed by the antidotes atropine (10â¯mg/kgâ¯i.p.) and/or pralidoxime (40â¯mg/kg; i.p.) given 1â¯h after poisoning. Pralidoxime partially reactivated the AChE activity in the prefrontal cortex, but not in the hippocampus and striatum. Atropine attenuated the depressive-like behaviour induced by chlorpyrifos in rats. Our results suggest that acute chlorpyrifos poisoning induces a transient depressive-like behaviour possible related to hippocampal AChE inhibition. They suggest that treatment with atropine and pralidoxime seems to be insufficient to counteract all the effects of OP acute poisoning, at least in rats.
Assuntos
Antídotos/farmacologia , Atropina/farmacologia , Encéfalo/efeitos dos fármacos , Clorpirifos/toxicidade , Depressão/prevenção & controle , Intoxicação por Organofosfatos/prevenção & controle , Acetilcolinesterase/metabolismo , Animais , Antídotos/administração & dosagem , Atropina/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Encéfalo/enzimologia , Depressão/induzido quimicamente , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Masculino , Intoxicação por Organofosfatos/etiologia , Compostos de Pralidoxima/administração & dosagem , Compostos de Pralidoxima/farmacologia , Ratos , Ratos WistarRESUMO
The neurotoxin MPTP has long been used to create a mouse model of Parkinson's disease (PD). Indeed, several MPTP analogues have been developed, including 2'-CH3-MPTP, which was shown to induce nigrostriatal DA neuronal depletion more potently than MPTP. However, no study on behavioral and molecular alterations in response to 2'-CH3-MPTP has been carried out so far. In the present work, 2'-CH3-MPTP was administered to mice (2.5, 5.0 and 10 mg/kg per injection, once a day, 5 days) and histological, biochemical, molecular and behavioral alterations were evaluated. We show that, despite a dose-dependent-like pattern observed for nigrostriatal dopaminergic neuronal death and dopamine depletion, dose-specific alterations in dopamine metabolism and in the expression of dopaminergic neurotransmission-associated genes could be related to specific motor deficits elicited by the different doses tested. Interestingly, 2'-CH3-MPTP leads to increased DAT and MAO-B transcription, which could explain, respectively, its higher potency and the requirement of higher doses of MAO inhibitors to prevent nigrostriatal neuronal death when compared to MPTP. Also, perturbations in dopamine metabolism as well as possible alterations in dopamine bioavailability in the synaptic cleft were also identified and correlated with strength and ambulation deficits in response to specific doses. Overall, the present work brings new evidence supporting the distinct effects of 2'-CH3-MPTP when compared to its analogue MPTP. Moreover, our data highlight the utmost importance of a precise experimental design, as different administration regimens and doses yield different biochemical, molecular and behavioral alterations, which can be explored to study specific aspects of PD.
Assuntos
1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/análogos & derivados , Neurotoxinas , Transtornos Parkinsonianos/induzido quimicamente , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/biossíntese , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Força da Mão , Ácido Homovanílico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Monoaminoxidase/biossíntese , Monoaminoxidase/genética , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismoRESUMO
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor dysfunction, cognitive deficits, and psychiatric symptoms. The primary genetic cause is an expansion of cytosine adenine guanine (CAG) nucleotides of the huntingtin gene, which codes an important protein involved with neuronal signaling. The severity of HD correlates with the number of CAG repeats and individuals with longer expansions have an earlier onset and more severe symptoms. A microarray study conducted by our research group showed alteration in DNAH6 gene (encoding dynein axonemal heavy chain 6). DNAH6 belongs to dynein family, whose members are constituents of the microtubule-associated motor proteins and is downregulated in the striatum of a HD mouse model (knockin HdhQ111/Q111). In this manner, our goal was to confirm these downregulations in the mouse model and verify if the same alteration in the axonemal DNAH6 gene expression is observed in blood samples of HD patients. Blood samples were collected from 17 patients with clinical diagnosis of HD and 12 healthy individuals and RNA extracted for qPCR analysis. Microarray data were confirmed by qPCR in knockin HdhQ111/Q111, and DNAH6 was severely decreased in those mice, as compared to control mice (HdhQ20/Q20). Notably, decreased expression of DNAH6 gene was also observed in HD patients when compared to control group and negatively correlates with the CAG expansion. Although further studies are necessary to underlie the molecular mechanisms of dynein-htt interaction, this data highlights DNAH6 as a potential new blood marker for HD.
Assuntos
Dineínas/sangue , Doença de Huntington/sangue , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Regulação para Baixo , Dineínas/genética , Dineínas/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/patologia , Camundongos , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Pesquisa Translacional BiomédicaRESUMO
Crack cocaine (crack) addiction represents a major social and health burden, especially seeing as users are more prone to engage in criminal and violent acts. Crack users show a higher prevalence of psychiatric comorbidities - particularly antisocial personality disorders - when compared to powder cocaine users. They also develop cognitive deficits related mainly to executive functions, including working memory. It is noteworthy that stimulant drugs can induce psychotic states, which appear to mimic some symptoms of schizophrenia among users. Social withdraw and executive function deficits are, respectively, negative and cognitive symptoms of schizophrenia mediated by reduced dopamine (DA) tone in the prefrontal cortex (PFC) of patients. That could be explained by an increased expression of D2R short isoform (D2S) in the PFC of such patients and/or by hypofunctioning NMDA receptors in this region. Reduced DA tone has already been described in the PFC of mice exposed to crack smoke. Therefore, it is possible that behavioral alterations presented by crack users result from molecular and biochemical neuronal alterations akin to schizophrenia. Accordingly, we found that upon crack inhalation mice have shown decreased social interaction and working memory deficits analogous to schizophrenia's symptoms, along with increased D2S/D2L expression ratio and decreased expression of NR1, NR2A and NR2B NMDA receptor subunits in the PFC. Herein we propose two possible mechanisms to explain the reduced DA tone in the PFC elicited by crack consumption in mice, bringing also the first direct evidence that crack use may result in schizophrenia-like neurochemical, molecular and behavioral alterations.
Assuntos
Cocaína Crack/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D2/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/induzido quimicamente , Animais , Modelos Animais de Doenças , Relações Interpessoais , Masculino , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/efeitos dos fármacos , Isoformas de Proteínas/metabolismo , Receptores de Dopamina D2/genética , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/complicações , Esquizofrenia/patologia , Psicologia do EsquizofrênicoRESUMO
Glutamate is the most important excitatory neurotransmitter of the mammalian central nervous system (CNS), playing an important role in memory, synaptic plasticity and neuronal development. However, glutamate overstimulation is also implicated in neuronal cell death. There are two major types of glutamate receptors: ionotropic and metabotropic. Thus far, eight metabotropic glutamate receptors (mGluRs) subtypes have been characterized and are divided into three subgroups based on sequence homology and cell signaling activation. mGluRs activate a wide variety of cell signaling pathways by G protein-coupled pathways or via G protein-independent cell signaling activation. Moreover, these receptors exhibit widespread distribution in the CNS and are implicated in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). This review aims to discuss the latest updates concerning mGluRs and their role in neurodegenerative diseases. mGluRs agonists and antagonists as well as positive and negative allosteric modulators have been tested in several animal models of neurodegenerative diseases. Furthermore, mGluR knockout mouse models have been crossed to mouse models of AD and HD, providing important data about mGluRs role in neurodegenerative disease progression. Thus, mGluRs constitute potential therapeutic targets for the development of therapies to treat neurodegenerative diseases.
Assuntos
Doenças Neurodegenerativas/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Ácido Glutâmico/metabolismo , Humanos , Neurotransmissores/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Parkinson's disease (PD) is the second most common neurodegenerative disease in the world, being characterized by dopaminergic neurodegeneration of substantia nigra pars compacta. PD pharmacotherapy has been based on dopamine replacement in the striatum with the dopaminergic precursor 3,4-dihydroxyphenylalanine (L-DOPA) and/or with dopaminergic agonists, alongside anticholinergic drugs in order to mitigate the motor abnormalities. However, these practices neither prevent nor stop the progression of the disease. Environmental enrichment (EE) has effectively prevented several neurodegenerative processes, mainly in preclinical trials. Several studies have demonstrated that EE induces biological changes, bearing on cognitive enhancement, neuroprotection, and on the attenuation of the effects of stress, anxiety, and depression. Herein, we investigated whether EE could prevent the motor, biochemical, and molecular abnormalities in a murine model of PD induced by 1-methyl-4-phenyl-2,3-dihydropyridine (MPTP). Our results show that EE does not prevent the dopaminergic striatal depletion induced by MPTP, despite having averted the MPTP-induced hyperlocomotion. However, it was able to slow down and avoid, respectively, the 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) depletion. Analysis of dopaminergic mRNA alterations in the midbrain showed that D1R expression was increased by MPTP, while the normal expression level of this receptor was restored by EE. As for the cholinergic system, MPTP led to a decrease in the ChAT gene expression while increasing the expression of both AChE and M1R. EE attenuated and prevented-respectively-ChAT and M1R gene expression alterations triggered by MPTP in the midbrain. Overall, our data brings new evidence supporting the neuroprotective potential of EE in PD, focusing on the interaction between dopaminergic and cholinergic systems.
Assuntos
Acetilcolina/metabolismo , Dopamina/metabolismo , Intoxicação por MPTP/metabolismo , Neurônios/metabolismo , Comportamento Social , Substância Negra/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Animais , Ácido Homovanílico/metabolismo , Locomoção , Intoxicação por MPTP/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Receptores Colinérgicos/genética , Receptores Colinérgicos/metabolismo , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/metabolismo , Substância Negra/citologia , Substância Negra/fisiopatologiaRESUMO
Chronic thiamine deficiency may be responsible for pathologic changes in the brains of alcoholics, and subclinical episodes of this vitamin deficiency may cause cumulative brain damage. In the present work, the chronic effects of ethanol and its association to a mild thiamine deficiency episode (subclinical model) on neocortical and hippocampal acetylcholinesterase activity were assessed along with their possible association to spatial cognitive dysfunction. The results indicate that in the beginning of the neurodegenerative process, before the appearance of brain lesions, chronic ethanol consumption reverses the effects of mild thiamine deficiency on both spatial cognitive performance and acetylcholinesterase activity without having significant effects on any morphometric parameter.
Assuntos
Acetilcolinesterase/metabolismo , Alcoolismo/metabolismo , Aprendizagem em Labirinto , Memória Espacial , Deficiência de Tiamina/metabolismo , Alcoolismo/complicações , Alcoolismo/fisiopatologia , Animais , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Neocórtex/metabolismo , Neocórtex/fisiopatologia , Ratos , Ratos Wistar , Deficiência de Tiamina/complicações , Deficiência de Tiamina/fisiopatologiaRESUMO
Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.
Assuntos
Modelos Animais de Doenças , Doença de Huntington/patologia , Corpos de Inclusão Intranuclear/patologia , Atividade Motora/fisiologia , Receptor de Glutamato Metabotrópico 5/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/fisiologia , Animais , Western Blotting , Proliferação de Células , Células Cultivadas , Perfilação da Expressão Gênica , Doença de Huntington/genética , Doença de Huntington/metabolismo , Técnicas Imunoenzimáticas , Corpos de Inclusão Intranuclear/genética , Corpos de Inclusão Intranuclear/metabolismo , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Piridinas/farmacologia , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tiazóis/farmacologiaRESUMO
Durante o processo adaptativo às condições locais as raças bovinas europeias introduzidas no Brasil na época da colonização, adquiriram características fisiológicas e fenotípicas que as diferenciaram das raças originais. O presente estudo teve como objetivo comparar a morfologia dos cromossomos sexuais de bovinos de quatro raças, naturalizadas brasileiras, bem como verificar a incidência de anomalias cromossômicas. Foi analisado o cariótipo de 332 animais de quatro raças: Caracu (115 fêmeas e 159 machos), Junqueira (13 fêmeas e 3 machos), Pantaneiro (8 machos) e Patuá (21 fêmeas e 13 machos), utilizando-se a coloração convencional de Giemsa. Os animais das raças estudadas apresentaram o complemento cromossômico normal da espécie (2n=60), constituído de 58 cromossomos autossomos de morfologia acrocêntrica e dois cromossomos sexuais X submetacêntricos nas fêmeas e um X e um Y nos machos. Na raça Caracu, as linhagens selecionadas para corte e para leite foram formadas por indivíduos portadores de cromossomo Y acrocêntrico e submetacêntrico, sendo que a linhagem de corte apresentou maior percentagem de cromossomo Y acrocêntrico (P<0,01). Em duas fêmeas e em dois machos nascidos de partos gemelares da raça Caracu, foi observado quimerismo 60,XX/60,XY. O cariótipo 60,XX/61,XXY foi observado em outra fêmea da mesma raça. Nas outras três raças, nenhuma anomalia cromossômica foi observada. A morfologia do cromossomo Y das raças Pantaneira e Patuá apresentou dimorfismo do cromossomo Y acrocêntrico e submetacêntrico. Na raça Junqueira, apenas a morfologia submetacêntrica foi observada.(AU)
During the adaptive process to Brazilian conditions, the native cattle breeds acquired physiological and phenotypic characteristics wich differs them from European breeds, from which they derive. The objectives of present study were to compare the sex chromosomes morphologies between four Brazilian native cattle breeds as well as the incidence of chromosomal abnormalities. The karyotype of 332 animals from four breeds were analyzed: Caracu (115 females and 159 males), Junqueira (13 females and 3 males), Pantaneiro (8 males) and Patua (21 females and 13 males). The Giemsa coloring were used to read the chromosome. All cattle breeds studied showed the normal chromosome (2n=60) consisting of 58 acrocentric autosomes and two submetacentric X chromosomes in females, and one X and one Y in males. In Caracu breed, selected for dairy or beef, it was developed by animals dimorphism carriers of Y chromosome (acrocentric and submetacentric), and the beef bloodlines showed higher percentage of acrocentric Y chromosome. There was 1% significant difference in Chi-Square test. In two females and two male born from twin birth of Caracu breed it was observed chemerism 60, XX/ 60, XY, and in other female from same breed it was observed 60, XX/ 61 XXY. For other three breeds, no chromosomal abnormality was observed. The Y chromosome morphology of the Pantaneiro and Patua breeds showed dimorphism of Y chromosome (submetacentric an acrocentric). In the Junqueira breed, only submetacentric morphology was observed.(AU)
Assuntos
Animais , Bovinos/classificação , Espécies Introduzidas , Adaptação a Desastres , Cromossomos/genética , Citogenética/tendênciasRESUMO
Durante o processo adaptativo às condições locais as raças bovinas europeias introduzidas no Brasil na época da colonização, adquiriram características fisiológicas e fenotípicas que as diferenciaram das raças originais. O presente estudo teve como objetivo comparar a morfologia dos cromossomos sexuais de bovinos de quatro raças, naturalizadas brasileiras, bem como verificar a incidência de anomalias cromossômicas. Foi analisado o cariótipo de 332 animais de quatro raças: Caracu (115 fêmeas e 159 machos), Junqueira (13 fêmeas e 3 machos), Pantaneiro (8 machos) e Patuá (21 fêmeas e 13 machos), utilizando-se a coloração convencional de Giemsa. Os animais das raças estudadas apresentaram o complemento cromossômico normal da espécie (2n=60), constituído de 58 cromossomos autossomos de morfologia acrocêntrica e dois cromossomos sexuais X submetacêntricos nas fêmeas e um X e um Y nos machos. Na raça Caracu, as linhagens selecionadas para corte e para leite foram formadas por indivíduos portadores de cromossomo Y acrocêntrico e submetacêntrico, sendo que a linhagem de corte apresentou maior percentagem de cromossomo Y acrocêntrico (P<0,01). Em duas fêmeas e em dois machos nascidos de partos gemelares da raça Caracu, foi observado quimerismo 60,XX/60,XY. O cariótipo 60,XX/61,XXY foi observado em outra fêmea da mesma raça. Nas outras três raças, nenhuma anomalia cromossômica foi observada. A morfologia do cromossomo Y das raças Pantaneira e Patuá apresentou dimorfismo do cromossomo Y acrocêntrico e submetacêntrico. Na raça Junqueira, apenas a morfologia submetacêntrica foi observada.
During the adaptive process to Brazilian conditions, the native cattle breeds acquired physiological and phenotypic characteristics wich differs them from European breeds, from which they derive. The objectives of present study were to compare the sex chromosomes morphologies between four Brazilian native cattle breeds as well as the incidence of chromosomal abnormalities. The karyotype of 332 animals from four breeds were analyzed: Caracu (115 females and 159 males), Junqueira (13 females and 3 males), Pantaneiro (8 males) and Patua (21 females and 13 males). The Giemsa coloring were used to read the chromosome. All cattle breeds studied showed the normal chromosome (2n=60) consisting of 58 acrocentric autosomes and two submetacentric X chromosomes in females, and one X and one Y in males. In Caracu breed, selected for dairy or beef, it was developed by animals dimorphism carriers of Y chromosome (acrocentric and submetacentric), and the beef bloodlines showed higher percentage of acrocentric Y chromosome. There was 1% significant difference in Chi-Square test. In two females and two male born from twin birth of Caracu breed it was observed chemerism 60, XX/ 60, XY, and in other female from same breed it was observed 60, XX/ 61 XXY. For other three breeds, no chromosomal abnormality was observed. The Y chromosome morphology of the Pantaneiro and Patua breeds showed dimorphism of Y chromosome (submetacentric an acrocentric). In the Junqueira breed, only submetacentric morphology was observed.
Assuntos
Animais , Adaptação a Desastres , Bovinos/classificação , Cromossomos/genética , Espécies Introduzidas , Citogenética/tendênciasRESUMO
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder characterized by involuntary body movement, cognitive impairment and psychiatric disturbance. A polyglutamine expansion in the amino-terminal region of the huntingtin (htt) protein is the genetic cause of HD. Htt protein interacts with a wide variety of proteins, and htt mutation causes cell signaling alterations in various neurotransmitter systems, including dopaminergic, glutamatergic, and cannabinoid systems, as well as trophic factor systems. This review will overview recent findings concerning htt-promoted alterations in cell signaling that involve different neurotransmitters and trophic factor systems, especially involving mGluR1/5, as glutamate plays a crucial role in neuronal cell death. The neuronal cell death that takes place in the striatum and cortex of HD patients is the most important factor underlying HD progression. Metabotropic glutamate receptors (mGluR1 and mGluR5) have a very controversial role in neuronal cell death and it is not clear whether mGluR1/5 activation either protects or exacerbates neuronal death. Thus, understanding how mutant htt protein affects glutamatergic receptor signaling will be essential to further establish a role for glutamate receptors in HD and develop therapeutic strategies to treat HD.
Assuntos
Doença de Huntington/fisiopatologia , Proteínas do Tecido Nervoso/metabolismo , Proteínas Nucleares/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Moduladores de Receptores de Canabinoides/metabolismo , Sobrevivência Celular , Ácido Glutâmico/metabolismo , Humanos , Proteína Huntingtina , Doença de Huntington/genética , Doença de Huntington/patologia , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/citologia , Neurônios/fisiologia , Proteínas Nucleares/genética , Peptídeos/genética , Receptores de Glutamato Metabotrópico/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/fisiologiaRESUMO
The aim of this study was to compare ovarian response and embryo production of superovulated Bos indicus and Bos taurus cows adapted to the environmental conditions from São Paulo State, Brazil. Ninety non-lactating cows from Caracu ( Bos taurus, n=40) and Nelore (Bos indicus, n=50) were treated with an intravaginal device containing progesterone (1.38 mg; CIDRB ®, Pfizer Animal Health, Montreal, Québec, Canada) and 2.5 mg, intramuscularly (IM), of estradiol benzoate (Estrogin®, Farmavet, São Paulo, Brazil). Four days later, all animals were treated with multiple IM injections of 400 IU of FSH (Pluset®, Calier, Spain) in decreasing doses (7575; 7550; 5025, and 2525 IU) at 12-h intervals over 4 days. On the seventh day, CIDR-B device was removed and cows received, IM, 150 ìg of cloprostenol (Veteglan®, Calier, Spain). Cows were then inseminated 48 and 62 h after cloprostenol treatment and embryos were recovered non-surgically seven days after first insemination. Differences in the number of corpora lutea (CL) number, total number of structures (ova/embryos), and number of transferable embryos were analyzed by Student t test. There was no difference (P > 0.05) in the average number of CL, total ova/embryos and transferable embryos of Caracu (11.4 ± 3.3; 8.6 ± 2.6 e 6.0 ± 2.4) and Nelore (12.0 ± 4.1; 9.0 ± 4.3 e 5.1 ± 2.9) cows, respectively. These results suggest that Cara
O objetivo do presente estudo foi comparar a resposta ovariana e produção de embriões de vacas Bos t. indicus e Bos t. taurus, adaptadas às condições ambientais do estado de São Paulo, Brasil, submetidas ao tratamento de superovulação. Noventa vacas das raças Caracu (Bos taurus, n=40) e Nelore (Bos indicus, n=50) recém desmamadas de suas crias, foram tratadas com um dispositivo vaginal contendo 1,38 g de progesterona (CIDR-B®, Pfizer, Brasil) e injeção, IM, de 2,5 mg de benzoato de estradiol (Estrogin®, Farmavet, Brasil). No quarto dia, iniciou-se o tratamento de superovulação utilizando 400 UI de pFSH (Pluset®, Calier, Espanha) IM em doses decrescentes (75-75; 75-50; 50-25; 25-25 IU) com intervalos de 12 horas. No sétimo dia foi retirado o CIDR-B e aplicados, IM, 150 mcg de cloprostenol (Veteglan®, Calier, Espanha). As vacas foram inseminadas duas vezes, 48 e 62 horas após o cloprostenol e a coleta não cirúrgica de embriões foi realizada sete dias após a primeira inseminação. As diferenças no número de corpos lúteos (CL), total de estruturas (ovócitos/embriões) e de embriões transferíveis foram analisadas pelo teste t de Student. Não houve diferença (P > 0,05) no número de CL, total de estruturas e de embriões transferíveis das vacas Caracu (11,4 ± 3,3; 8,6 ± 2,6 e 6,0 ± 2,4) e Nelore (12,0 ± 4,1; 9,0 ± 4,3 e 5,1 ± 2,9), respectivamente. Esses resultados são indicativos que
RESUMO
The aim of this study was to compare ovarian response and embryo production of superovulated Bos indicus and Bos taurus cows adapted to the environmental conditions from São Paulo State, Brazil. Ninety non-lactating cows from Caracu ( Bos taurus, n=40) and Nelore (Bos indicus, n=50) were treated with an intravaginal device containing progesterone (1.38 mg; CIDRB ®, Pfizer Animal Health, Montreal, Québec, Canada) and 2.5 mg, intramuscularly (IM), of estradiol benzoate (Estrogin®, Farmavet, São Paulo, Brazil). Four days later, all animals were treated with multiple IM injections of 400 IU of FSH (Pluset®, Calier, Spain) in decreasing doses (7575; 7550; 5025, and 2525 IU) at 12-h intervals over 4 days. On the seventh day, CIDR-B device was removed and cows received, IM, 150 ìg of cloprostenol (Veteglan®, Calier, Spain). Cows were then inseminated 48 and 62 h after cloprostenol treatment and embryos were recovered non-surgically seven days after first insemination. Differences in the number of corpora lutea (CL) number, total number of structures (ova/embryos), and number of transferable embryos were analyzed by Student t test. There was no difference (P > 0.05) in the average number of CL, total ova/embryos and transferable embryos of Caracu (11.4 ± 3.3; 8.6 ± 2.6 e 6.0 ± 2.4) and Nelore (12.0 ± 4.1; 9.0 ± 4.3 e 5.1 ± 2.9) cows, respectively. These results suggest that Caracu and Nelore cows superovulatedin tropical climate had similar ovarian responses and embryo production.
O objetivo do presente estudo foi comparar a resposta ovariana e produção de embriões de vacas Bos t. indicus e Bos t. taurus, adaptadas às condições ambientais do estado de São Paulo, Brasil, submetidas ao tratamento de superovulação. Noventa vacas das raças Caracu (Bos taurus, n=40) e Nelore (Bos indicus, n=50) recém desmamadas de suas crias, foram tratadas com um dispositivo vaginal contendo 1,38 g de progesterona (CIDR-B®, Pfizer, Brasil) e injeção, IM, de 2,5 mg de benzoato de estradiol (Estrogin®, Farmavet, Brasil). No quarto dia, iniciou-se o tratamento de superovulação utilizando 400 UI de pFSH (Pluset®, Calier, Espanha) IM em doses decrescentes (75-75; 75-50; 50-25; 25-25 IU) com intervalos de 12 horas. No sétimo dia foi retirado o CIDR-B e aplicados, IM, 150 mcg de cloprostenol (Veteglan®, Calier, Espanha). As vacas foram inseminadas duas vezes, 48 e 62 horas após o cloprostenol e a coleta não cirúrgica de embriões foi realizada sete dias após a primeira inseminação. As diferenças no número de corpos lúteos (CL), total de estruturas (ovócitos/embriões) e de embriões transferíveis foram analisadas pelo teste t de Student. Não houve diferença (P > 0,05) no número de CL, total de estruturas e de embriões transferíveis das vacas Caracu (11,4 ± 3,3; 8,6 ± 2,6 e 6,0 ± 2,4) e Nelore (12,0 ± 4,1; 9,0 ± 4,3 e 5,1 ± 2,9), respectivamente. Esses resultados são indicativos que vacas Nelore e Caracu manejadas esuperovuladas em ambiente tropical apresentam resposta ovariana e produção de embriões semelhante.
Assuntos
Animais , Bovinos , Reprodução , Superovulação , Transferência Embrionária/veterináriaRESUMO
Overwhelming evidence supports the importance of the sympathetic nervous system in heart failure. In contrast, much less is known about the role of failing cholinergic neurotransmission in cardiac disease. By using a unique genetically modified mouse line with reduced expression of the vesicular acetylcholine transporter (VAChT) and consequently decreased release of acetylcholine, we investigated the consequences of altered cholinergic tone for cardiac function. M-mode echocardiography, hemodynamic experiments, analysis of isolated perfused hearts, and measurements of cardiomyocyte contraction indicated that VAChT mutant mice have decreased left ventricle function associated with altered calcium handling. Gene expression was analyzed by quantitative reverse transcriptase PCR and Western blotting, and the results indicated that VAChT mutant mice have profound cardiac remodeling and reactivation of the fetal gene program. This phenotype was attributable to reduced cholinergic tone, since administration of the cholinesterase inhibitor pyridostigmine for 2 weeks reversed the cardiac phenotype in mutant mice. Our findings provide direct evidence that decreased cholinergic neurotransmission and underlying autonomic imbalance cause plastic alterations that contribute to heart dysfunction.
Assuntos
Colinérgicos/metabolismo , Insuficiência Cardíaca/metabolismo , Disautonomias Primárias/fisiopatologia , Transmissão Sináptica/fisiologia , Remodelação Ventricular/fisiologia , Animais , Cálcio/metabolismo , Ecocardiografia , Insuficiência Cardíaca/fisiopatologia , Frequência Cardíaca/fisiologia , Hemodinâmica , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Técnicas de Patch-Clamp , Fenótipo , Receptores Acoplados a Proteínas G/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Sistema Nervoso Simpático/metabolismo , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismoRESUMO
At 1985, a Brown Swiss herd from the Institute of Animal Science and Pastures, APTA/ SAA was cytogenetically analyzed and 1/29 Robertsonian translocation was observed. Such anomaly is related to fertility reduction. Quimeric abnormality such as 60,XX/60,XY in freemartin females. This study aimed to evaluate the incidence of cromossomic abnormalities in Brown Swiss animals, descending form herd karyotyped earlier. After 25 years, 127 animals (97 females and 30 males) from this herd were karyotyped by metaphases obtained from blood lymphocyte cultures. The typical diploid number 2n=60, 58 acrocentric and two X submetacentric chromosomes were confirmed in 94 females and in 27 males the sexual complement X and Y, both submetacentric, although from different sizes. Four females from gemelar parturition whit males were karyotyped. Three of them presented quimerism 60,XX/60,XY (one with 25.8% of female cells (XX) and 74.2% male cells (XY); one another with 10% of cells XX e 90% of XY and the third with 50% of each type) showing genital masculinization, diagnosed as freemartism and discarded from herd. Two hundred and five cells were analyzed from another female twins and only 60,XX cells were found, diagnosed as normal. His sister also were normal (60,XY). The another three males were also analyzed from gemelar heterosexual parturition, with karyotype 60,XX/60,XY. Cytogenetic analysis
Em 1985 o plantel de bovinos da raça Pardo-Suíça do Instituto de Zootecnia, da Secretaria da Agricultura e Abastecimento de São Paulo (SAA/SP), APTA, foi analisado citogeneticamente e verificado a presença de translocação Robertsoniana 1/29, anomalia está relacionada com a redução da fertilidade. Neste plantel foi detectado também quimerismo 60,XX/60,XY em fêmeas freemartin e em macho gêmeo. O presente estudo teve como objetivo analisar a incidência de anomalias cromossômicas, em animais da raça Pardo-Suíça, descendentes daqueles cariotipados anteriormente. Após 25 anos, 127 bovinos sendo 97 fêmeas e 30 machos, progênies do plantel anterior foram cariotipados através de metáfases obtidas de cultura de linfócitos de sangue periférico. O número diplóide típico dos bovinos de 2n=60 e o cariótipo constituído de 58 autossomos acrocêntricos e dois cromossomos X submetacêntricos foram confirmados em 94 fêmeas, e em 27 machos o complemento sexual formado por um cromossomo X e um Y, ambos submetacêntricos, mas de tamanhos diferentes. Quatro fêmeas nascidas de partos gemelares com machos foram cariotipadas, três apresentaram quimerismo 60,XX/60,XY em suas células sanguíneas (uma com 25,8% de células femininas (XX) e 74,2% de células masculinas (XY); outra 10% de células XX e 90% de XY e a terceira 50% de células de cada tipo), masculinização dos órgãos genitais, sendo diagnosticada com
RESUMO
At 1985, a Brown Swiss herd from the Institute of Animal Science and Pastures, APTA/SAA was cytogenetically analyzed and 1/29 Robertsonian translocation was observed. Such anomalyis related to fertility reduction. Quimeric abnormality such as 60,XX/60,XY in freemartin females.This study aimed to evaluate the incidence of cromossomic abnormalities in Brown Swiss animals,descending form herd karyotyped earlier. After 25 years, 127 animals (97 females and 30 males)from this herd were karyotyped by metaphases obtained from blood lymphocyte cultures. Thetypical diploid number 2n=60, 58 acrocentric and two X submetacentric chromosomes were confirmed in 94 females and in 27 males the sexual complement X and Y, both submetacentric,although from different sizes. Four females from gemelar parturition whit males were karyotyped.Three of them presented quimerism 60,XX/60,XY (one with 25.8% of female cells (XX) and 74.2%male cells (XY); one another with 10% of cells XX e 90% of XY and the third with 50% of each type)showing genital masculinization, diagnosed as freemartism and discarded from herd. Two hundredand five cells were analyzed from another female twins and only 60,XX cells were found, diagnosedas normal. His sister also were normal (60,XY). The another three males were also analyzed fromgemelar heterosexual parturition, with karyotype 60,XX/60,XY. Cytogenetic analysis are a safemethodology for freemartin abnormalities identification in female bovine twins with male bovine,giving the opportunity of selecting fertile animals, avoiding loses in the management of sterileanimals. Robertsonian's translocation was not observed in any of the animals analyzed.
Em 1985 o plantel de bovinos da raça Pardo-Suíça do Instituto de Zootecnia, da Secretaria da Agricultura e Abastecimento de São Paulo (SAA/SP), APTA, foi analisado citogeneticamentee verificado a presença de translocação Robertsoniana 1/29, anomalia está relacionada com a redução da fertilidade. Neste plantel foi detectado também quimerismo 60,XX/60,XY em fêmeas"freemartin" e em macho gêmeo. O presente estudo teve como objetivo analisar a incidência deanomalias cromossômicas, em animais da raça Pardo-Suíça, descendentes daqueles cariotipadosanteriormente. Após 25 anos, 127 bovinos sendo 97 fêmeas e 30 machos, progênies do plantel ante-rior foram cariotipados através de metáfases obtidas de cultura de linfócitos de sangue periférico.O número diplóide típico dos bovinos de 2n=60 e o cariótipo constituído de 58 autossomosacrocêntricos e dois cromossomos X submetacêntricos foram confirmados em 94 fêmeas, e em 27machos o complemento sexual formado por um cromossomo X e um Y, ambos submetacêntricos,mas de tamanhos diferentes. Quatro fêmeas nascidas de partos gemelares com machos foramcariotipadas, três apresentaram quimerismo 60,XX/60,XY em suas células sanguíneas (uma com 25,8% de células femininas (XX) e 74,2% de células masculinas (XY); outra 10% de células XX e 90%de XY e a terceira 50% de células de cada tipo), masculinização dos órgãos genitais, sendodiagnosticada como freemartismo e descartadas do plantel por serem consideradas estéreis. Seustrês irmãos também apresentaram cariótipos 60,XX/60,XY. Duzentos e cinco células foram analisa-das da outra fêmea gêmea, e apenas células tipo 60,XX foram encontradas, sendo diagnosticadacomo normal, seu irmão gêmeo apresentou somente células 60,XY. Análise citogenética é um método seguro para diagnóstico de freemartismo em fêmeas bovinas gêmeas com macho, fornecendo aoportunidade ao produtor de retirar portadores de quimerismo, do processo reprodutivo, diminuindo eventuais prejuízos com o manejo de animais estéreis. Translocação Robertsoniana não foidetectada em nenhum animal analisado.