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An outbreak of mumps within a student population in Scotland was investigated to assess the effect of previous vaccination on infection and clinical presentation, and any genotypic variation. Of the 341 cases, 79% were aged 18-24. Vaccination status was available for 278 cases of whom 84% had received at least one dose of mumps containing vaccine and 62% had received two. The complication rate was 5·3% (mainly orchitis), and 1·2% were admitted to hospital. Genetic sequencing of mumps virus isolated from cases across Scotland classified 97% of the samples as genotype G. Two distinct clusters of genotype G were identified, one circulating before the outbreak and the other thereafter, suggesting the virus that caused this outbreak was genetically different from the previously circulating virus. Whilst the poor vaccine effectiveness we found may be due to waning immunity over time, a contributing factor may be that the current mumps vaccine is less effective against some genotypes. Although the general benefits of the measles-mumps-rubella (MMR) vaccine should continue to be promoted, there may be value in reassessing the UK vaccination schedule and the current mumps component of the MMR vaccine.
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Surtos de Doenças/estatística & dados numéricos , Vacina contra Caxumba/uso terapêutico , Vírus da Caxumba/genética , Caxumba/epidemiologia , Estudantes/estatística & dados numéricos , Adolescente , Surtos de Doenças/prevenção & controle , Feminino , Variação Genética/genética , Humanos , Masculino , Caxumba/imunologia , Caxumba/prevenção & controle , Caxumba/virologia , Vacina contra Caxumba/imunologia , Vírus da Caxumba/imunologia , Reação em Cadeia da Polimerase em Tempo Real , Escócia/epidemiologia , Adulto JovemRESUMO
In 2003 the Motor Neurone Disease (MND) Association, together with The Wellcome Trust, funded the creation of a national DNA Bank specific for MND. It was anticipated that the DNA Bank would constitute an important resource to researchers worldwide and significantly increase activity in MND genetic research. The DNA Bank houses over 3000 high quality DNA samples, all of which were donated by people living with MND, family members and non-related controls, accompanied by clinical phenotype data about the patients. Today the primary focus of the UK MND DNA Bank still remains to identify causative and disease modifying factors for this devastating disease.
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Bancos de Espécimes Biológicos , DNA , Doença dos Neurônios Motores/genética , Bancos de Espécimes Biológicos/normas , Humanos , Controle de Qualidade , Manejo de Espécimes , Reino UnidoRESUMO
Objective: To develop and pilot a web-based patient decision aid (PDA) to support people living with motor neurone disease (plwMND) considering having a gastrostomy tube placed. Methods: In Phase 1, content and design were informed by semi-structured interviews, literature reviews and a prioritization survey. In Phase 2, the prototype PDA was tested with users and developed iteratively with feedback from surveys and 'think-aloud' interviews. Phase 1 and 2 participants were plwMND, carers and healthcare professionals (HCPs). In Phase 3, the PDA was evaluated by plwMND using validated questionnaires and HCPs provided feedback in focus groups. Results: Sixteen plwMND, 16 carers and 25 HCPs took part in Phases 1 and 2. Interviews and the literature review informed a prioritization survey with 82 content items. Seventy-seven per cent (63/82) of the content of the PDA was retained. A prototype PDA, which conforms to international standards, was produced and improved during Phase 2. In Phase 3, 17 plwMND completed questionnaires after using the PDA. Most plwMND (94%) found the PDA completely acceptable and would recommend it to others in their position, 88% had no decisional conflict, 82% were well prepared and 100% were satisfied with their decision-making. Seventeen HCPs provided positive feedback and suggestions for use in clinical practice. Conclusion: Gastrostomy Tube: Is it for me? was co-produced with stakeholders and found to be acceptable, practical and useful. Freely available from the MND Association website, the PDA is a valuable tool to support the shared decision-making process for gastrostomy tube placement.
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BACKGROUND: Targeted delivery of the angiogenic factor, vascular endothelial growth factor (VEGF), to motor neurons prolongs survival in rodent models of amyotrophic lateral sclerosis (ALS), while mice expressing reduced VEGF concentrations develop motor neuron degeneration reminiscent of ALS, raising the question whether VEGF contributes to the pathogenesis of ALS. An initial association study reported that VEGF haplotypes conferred increased susceptibility to ALS in humans, but later studies challenged this initial finding. METHODS AND FINDINGS: A meta-analysis was undertaken to critically reappraise whether any of the three common VEGF gene variations (-2578C/A, -1154G/A and -634G/C) increase the risk of ALS. Over 7000 subjects from eight European and three American populations were included in the analysis. Pooled odds ratios were calculated using fixed-effects and random-effects models, and four potential sources of heterogeneity (location of disease onset, gender, age at disease onset and disease duration) were assessed. After correction, none of the genotypes or haplotypes was significantly associated with ALS. Subgroup analysis by gender revealed, however, that the -2578AA genotype, which lowers VEGF expression, increased the risk of ALS in males (OR = 1.46 males vs females; 95% CI = 1.19 to 1.80; p = 7.8 10E-5), even after correction for publication bias and multiple testing. CONCLUSIONS: This meta-analysis does not support the original conclusion that VEGF haplotypes increase the risk of ALS in humans, but the significant association of the low-VEGF -2578AA genotype with increased susceptibility to ALS in males reappraises the link between reduced VEGF concentrations and ALS, as originally revealed by the fortuitous mouse genetic studies.
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Esclerose Lateral Amiotrófica/genética , Fator A de Crescimento do Endotélio Vascular/genética , Esclerose Lateral Amiotrófica/patologia , Animais , Modelos Animais de Doenças , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Camundongos , Neurônios Motores/patologia , Polimorfismo de Nucleotídeo Único , Fatores SexuaisRESUMO
On March 19, 2019, the United States Food and Drug Administration (FDA) approved Zulresso (brexanolone) for intravenous use for the treatment of postpartum depression (PPD) in adult women. The decision was based on three recent clinical trials following an FDA priority review and breakthrough therapy designation. Brexanolone is now available through a restricted process called the Zulresso Risk Evaluation and Mitigation Strategy Program that requires the drug to be administered by a healthcare provider in a certified healthcare facility. Brexanolone represents an important new treatment option to address treatment-resistant depressive symptoms. In this article, we discuss the current critical need for PPD treatments, the mechanisms of brexanolone action, and the efficacy and drug safety studies that led to FDA approval. Additionally, we discuss some limitations of the current formulation, specific populations of women that might benefit from this treatment, and how new drugs on the horizon may increase the ability to treat PPD in a variety of patient populations.
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Depressão Pós-Parto/tratamento farmacológico , Pregnanolona/uso terapêutico , beta-Ciclodextrinas/uso terapêutico , Aprovação de Drogas , Combinação de Medicamentos , Feminino , Humanos , Estados Unidos , United States Food and Drug AdministrationRESUMO
Iron misregulation promotes oxidative stress, a proposed pathological mechanism in neurodegenerative disease. The aim of this study was to evaluate serum iron metabolism indicators in 60 amyotrophic lateral sclerosis (ALS) patients and 44 age matched controls. Serum ferritin levels were significantly increased in ALS patients compared to controls (p < 0.001), while no differences in the levels of serum iron, transferrin, iron saturation or total iron binding capacity were found. Likewise no differences in C reactive protein (CRP) or caeruloplasmin were detected, suggesting that the elevated ferritin levels in ALS did not merely indicate an acute phase response. The increased ferritin level may reflect a general increase in stored iron or be a consequence of ongoing muscle degeneration.
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Esclerose Lateral Amiotrófica/sangue , Ferritinas/sangue , Idoso , Envelhecimento , Análise de Variância , Proteína C-Reativa/metabolismo , Ceruloplasmina/metabolismo , Feminino , Humanos , Ferro/sangue , Ferro/metabolismo , Masculino , Pessoa de Meia-Idade , Distribuição Normal , Caracteres SexuaisRESUMO
YACs from the complex repetitive human genomic region 5q13, spanning the spinal muscular atrophy (SMA) locus, have been searched for transcribed sequences using the method of End Ligation Coincident Sequence Cloning. Six transcripts (PT1-6) have been identified, three of which (PT4, PT5 and PT6) are novel. Five of these elements hybridise to multiple loci in 5q13, but PT5 is single copy and maps very close to markers that show linkage disequilibrium with SMA.
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Cromossomos Humanos Par 5/genética , Atrofia Muscular Espinal/genética , RNA Mensageiro/genética , Transcrição Gênica , Sequência de Bases , Cromossomos Artificiais de Levedura , Clonagem Molecular , Marcadores Genéticos , Humanos , Dados de Sequência Molecular , RNA Mensageiro/análise , Sequências Repetitivas de Ácido Nucleico , Homologia de Sequência do Ácido Nucleico , Distribuição TecidualRESUMO
Humans and other animals show a remarkable capacity for resilience following traumatic, stressful events. Resilience is thought to be an active process related to coping with stress, although the cellular and molecular mechanisms that support active coping and stress resistance remain poorly understood. In this review, we focus on the neurobiological mechanisms by which environmental and social experiences promote stress resistance. In male Syrian hamsters, exposure to a brief social defeat stressor leads to increased avoidance of novel opponents, which we call conditioned defeat. Also, hamsters that have achieved dominant social status show reduced conditioned defeat as well as cellular and molecular changes in the neural circuits controlling the conditioned defeat response. We propose that experience-dependent neural plasticity occurs in the prelimbic (PL) cortex, infralimbic (IL) cortex, and ventral medial amygdala (vMeA) during the maintenance of dominance relationships, and that adaptations in these neural circuits support stress resistance in dominant individuals. Overall, behavioral treatments that promote success in competitive interactions may represent valuable interventions for instilling resilience.
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Adaptação Psicológica/fisiologia , Encéfalo/fisiopatologia , Plasticidade Neuronal/fisiologia , Resiliência Psicológica , Estresse Psicológico/fisiopatologia , Animais , HumanosRESUMO
BACKGROUND: GTP cyclohydrolase I (GCH1) mutations are the commonest cause of Dopa-responsive dystonia (DRD). Clinical phenotypes can be broad, even within a single family. METHODS: We present clinical, genetic and functional imaging data on a British kindred in which affected subjects display phenotypes ranging from DRD to Parkinson's disease (PD). Twelve family members were studied. Clinical examination, dopamine transporter (DAT) imaging, and molecular genetic analysis of GCH1 and the commonest known familial PD-related genes were performed. RESULTS: We have identified a novel missense variant, c.5A > G, p.(Glu2Gly), within the GCH1 gene in affected family members displaying a range of phenotypes. Two affected subjects carrying this variant had abnormal DAT imaging. These two with abnormal DAT imaging had a PD phenotype, while the remaining three subjects with the novel GCH1 variant had normal DAT imaging and a DRD phenotype. CONCLUSIONS: We propose that this GCH1 variant is pathogenic in this family and these findings suggest that similar mechanisms involving abnormal GTP cyclohydolase I may underlie both PD and DRD. GCH1 genetic testing should be considered in patients with PD and a family history of DRD.
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Distúrbios Distônicos/genética , GTP Cicloidrolase/genética , Doença de Parkinson/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Distúrbios Distônicos/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Doença de Parkinson/fisiopatologia , Linhagem , FenótipoRESUMO
The term spinal muscular atrophy (SMA) is used to encompass a group of inherited disorders in which the striking pathological feature is loss of the cell bodies of alpha motor neurons in the anterior horn cell of the spinal cord and, in some cases, of the bulbar motor nuclei. Although the pathological features of these disorders have been well characterized, the nature of the primary underlying biochemical abnormality remains to be determined. In the 1990s genetic linkage was established for the childhood onset recessive forms of SMA (types I, II and III) to markers mapping to the chromosomal region 5q11.2-13.3. Physical maps of the region were then constructed, several candidate genes isolated and in 1995 deletions in two genes, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene, were identified in significant numbers of patients. Already the impact of the characterization of these deletions is being seen in clinical practice in terms of aiding diagnosis in symptomatic cases and in prenatal diagnosis. As discussed in this review however, several questions remain unresolved. It is unclear whether deletions in one or both of these genes, or indeed in other, as yet unidentified, genes are important in generating the SMA phenotype. The function of the protein product of the SMN gene is unknown. The NAIP gene encodes a protein which inhibits apoptosis in a mammalian cell line: is it disruption of this function which is relevant in SMA? What underlies the variation in disease severity evident both between and within families? Resolution of such issues is of crucial importance if the identification of these deleted gene sequences is to lead to the development of rational therapies for motor neuron diseases.
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Deleção de Genes , Atrofia Muscular Espinal/genética , Aberrações Cromossômicas/genética , Transtornos Cromossômicos , Clonagem Molecular , Doenças Genéticas Inatas/genética , Humanos , Neurônios Motores/fisiologia , Proteínas do Tecido Nervoso/genética , Proteína Inibidora de Apoptose NeuronalRESUMO
The survival motor neuron (SMN) gene is present in two copies on chromosome 5q13 and the evidence is now compelling that mutations in the telomeric copy (SMNt) of the gene underlie childhood onset proximal spinal muscular atrophy (SMA). There is a correlation between the number of centromeric SMN gene copies (SMNc) and the clinical severity of the disease but this relationship is not absolute. Allelic variants of the apolipoprotein E (APOE) gene encoded on chromosome 19q are known to influence the prognosis and risk in a number of neurological disorders. We have therefore genotyped 166 unrelated cases of SMA to determine whether the presence of specific APOE genotypes correlates with severity of disease. The study failed to show the influence of any particular APOE genotype on disease severity, with specifically APOE epsilon4 being no more common in the milder SMA forms and APOE epsilon2 not over represented in type I SMA. A limited study of 23 SMA families also failed to show any influence of APOE genotype on SMA disease severity. Factors other than APOE genotype must therefore be responsible for determining SMA disease severity.
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Apolipoproteínas E/genética , Cromossomos Humanos Par 19 , Atrofias Musculares Espinais da Infância/genética , Atrofias Musculares Espinais da Infância/fisiopatologia , Apolipoproteína E2 , Apolipoproteína E3 , Apolipoproteína E4 , Criança , Mapeamento Cromossômico , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , FenótipoRESUMO
The affinity constant for doxepin obtained from inhibition of histamine-induced contraction of guinea-pig intestinal smooth muscle at 30 degrees C was 2.6 +/- 0.18 X 10(10)M-1. The slope of a Schild plot was not significantly different from unity. The affinity constant of doxepin did not vary markedly with temperature. At 37 degrees C it was 3.75 +/- 0.02 X 10(10)M-1 and at 25 degrees C 2.1 X 10(10)M-1. Doxepin was a competitive inhibitor of [3H]-mepyramine binding to guinea-pig cerebellar homogenates. The affinity constant derived for doxepin at 30 degrees C was 1.12 +/- 0.45 X 10(10)M-1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]-mepyramine binding in guinea-pig cerebellum, cerebral cortex and hippocampus did not differ significantly from unity. The mean affinity of mepyramine for histamine H1-receptors in rat brain homogenates at 30 degrees C was 3.5 X 10(8)M-1. Hill coefficients for curves of doxepin or mepyramine inhibition of [3H]-mepyramine binding to homogenates of rat cerebral cortex or rat whole brain were near unity. These studies provide no evidence that doxepin binds preferentially to a sub-class of histamine H1-receptors in rat brain.
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Encéfalo/metabolismo , Doxepina/metabolismo , Receptores Histamínicos H1/metabolismo , Receptores Histamínicos/metabolismo , Animais , Ligação Competitiva/efeitos dos fármacos , Córtex Cerebral/metabolismo , Feminino , Cobaias , Técnicas In Vitro , Intestinos/efeitos dos fármacos , Cinética , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Pirilamina/metabolismo , Pirilamina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
Amyotrophic lateral sclerosis (ALS) is a progressive neurological disorder characterised by degeneration of upper and lower motor neurons. Whilst the primary pathogenic trigger is unknown in most cases, evidence is mounting to implicate a role for glutamate-mediated neurotoxicity in the disorder. Recent studies have shown reduced levels of the mainly astroglial glutamate transporter EAAT2 in ALS motor cortex and spinal cord and multiple abnormal EAAT2 mRNA species in ALS brain tissue. One cause of the low EAAT2 levels may be that point mutations in the EAAT2 gene, EAAT2, result in an abnormal unstable protein. To test this hypothesis we analysed EAAT2 in 128 sporadic and 23 familial European ALS cases. No variants within the coding sequence of EAAT2 to affect the protein sequence nor in the consensus splice sites of the flanking intronic sequences were found in any cases, similar to findings in other reports. Frequent polymorphisms within the flanking intronic sequences of both exons 2 and 4 were seen but at similar frequencies in controls. Mechanisms other than mutations within the coding region of EAAT2 must therefore be responsible for the low levels of EAAT2 seen in most cases of ALS.
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Esclerose Lateral Amiotrófica/genética , Polimorfismo Genético/genética , Receptores de Neurotransmissores/genética , Sequência de Bases/genética , Eletroforese em Gel de Poliacrilamida , Europa (Continente) , Transportador 2 de Aminoácido Excitatório , Éxons/genética , Humanos , Reação em Cadeia da Polimerase , Polimorfismo Conformacional de Fita SimplesRESUMO
Chronic inflammatory demyelinating polyneuropathy is a disorder typified clinically by motor and sensory neuropathy of at least 2 months' duration and pathologically by multifocal inflammatory demyelination. Its usual presentation is with features reflecting the polyneuropathy, namely limb weakness with hyporeflexia or areflexia and sensory symptoms of glove and stocking distribution. In this report, we detail the course of a 53-year-old man who presented to our neurological service with a severe headache in association with papilledema. The initial diagnosis considered was of possible primary intracranial pathology. Two months later, he developed limb weakness and sensory symptoms typical of chronic inflammatory demyelinating polyneuropathy. His headache, papilledema, and limb symptoms responded to oral corticosteroid therapy, the standard treatment for this type of neuropathy. We hypothesize that his headache and papilledema were due to the elevated cerebrospinal fluid protein level as a result of the polyneuropathy. To our knowledge, this is the first report of headache being a prominent and early symptom of this disorder.
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Cefaleia/etiologia , Papiledema/etiologia , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/complicações , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/diagnóstico , Corticosteroides/uso terapêutico , Cefaleia/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Papiledema/diagnóstico , Polirradiculoneuropatia Desmielinizante Inflamatória Crônica/tratamento farmacológico , Prednisolona/uso terapêuticoRESUMO
Water problems have a human dimension where the ideas, perceptions, values and life-styles of individuals in their different roles have an impact. A many-sided set of stakeholders is preferable in any decision process, with empowerment of those less able to make their views known.
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Conservação dos Recursos Naturais , Tomada de Decisões , Meio Ambiente , Abastecimento de Água , Defesa do Consumidor , Humanos , Estilo de VidaRESUMO
Puberty is a critical period of development during which the reemergence of gonadotropin-releasing hormone secretion from the hypothalamus triggers a cascade of hormone-dependent processes. Maturation of specific brain regions including the prefrontal cortex occurs during this window, but the complex mechanisms underlying these dynamic changes are not well understood. Particularly, the potential involvement of epigenetics in this programming has been under-examined. The epigenome is known to guide earlier stages of development, and it is similarly poised to regulate vital pubertal-driven brain maturation. Further, as epigenetic machinery is highly environmentally responsive, its involvement may also lend this period of growth to greater vulnerability to external insults, resulting in reprogramming and increased disease risk. Importantly, neuropsychiatric diseases commonly present in individuals during or immediately following puberty, and environmental perturbations including stress may precipitate disease onset by disrupting the normal trajectory of pubertal brain development via epigenetic mechanisms. In this review, we discuss epigenetic processes involved in pubertal brain maturation, the potential points of derailment, and the importance of future studies for understanding this dynamic developmental window and gaining a better understanding of neuropsychiatric disease risk.
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Encéfalo/crescimento & desenvolvimento , Epigênese Genética , Puberdade/genética , Feminino , Humanos , MasculinoRESUMO
BACKGROUND: Lithium has neuroprotective effects in cell and animal models of amyotrophic lateral sclerosis (ALS), and a small pilot study in patients with ALS showed a significant effect of lithium on survival. We aimed to assess whether lithium improves survival in patients with ALS. METHODS: The lithium carbonate in amyotrophic lateral sclerosis (LiCALS) trial is a randomised, double-blind, placebo-controlled trial of oral lithium taken daily for 18 months in patients with ALS. Patients aged at least 18 years who had ALS according to the revised El Escorial criteria, had disease duration between 6 and 36 months, and were taking riluzole were recruited from ten centres in the UK. Patients were randomly assigned (1:1) to receive either lithium or matched placebo tablets. Randomisation was via an online system done at the level of the individual by block randomisation with randomly varying block sizes, stratified by study centre and site of disease onset (limb or bulbar). All patients and assessing study personnel were masked to treatment assignment. The primary endpoint was the rate of survival at 18 months and was analysed by intention to treat. This study is registered with Eudract, number 2008-006891-31. FINDINGS: Between May 26, 2009, and Nov 10, 2011, 243 patients were screened, 214 of whom were randomly assigned to receive lithium (107 patients) or placebo (107 patients). Two patients discontinued treatment and one died before the target therapeutic lithium concentration could be achieved. 63 (59%) of 107 patients in the placebo group and 54 (50%) of 107 patients in the lithium group were alive at 18 months. The survival functions did not differ significantly between groups (Mantel-Cox log-rank χ(2) on 1 df=1·64; p=0·20). After adjusting for study centre and site of onset using logistic regression, the relative odds of survival at 18 months (lithium vs placebo) was 0·71 (95% CI 0·40-1·24). 56 patients in the placebo group and 61 in the lithium group had at least one serious adverse event. INTERPRETATION: We found no evidence of benefit of lithium on survival in patients with ALS, but nor were there safety concerns, which had been identified in previous studies with less conventional designs. This finding emphasises the importance of pursuing adequately powered trials with clear endpoints when testing new treatments. FUNDING: The Motor Neurone Disease Association of Great Britain and Northern Ireland.
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Esclerose Lateral Amiotrófica/tratamento farmacológico , Esclerose Lateral Amiotrófica/mortalidade , Idoso , Método Duplo-Cego , Feminino , Humanos , Carbonato de Lítio/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fármacos Neuroprotetores/uso terapêutico , Taxa de Sobrevida/tendências , Resultado do TratamentoRESUMO
Although exposure to social stress leads to increased depression-like and anxiety-like behavior, some individuals are more vulnerable than others to these stress-induced changes in behavior. Prior social experience is one factor that can modulate how individuals respond to stressful events. In this study, we investigated whether experience-dependent resistance to the behavioral consequences of social defeat was associated with a specific pattern of neural activation. We paired weight-matched male Syrian hamsters in daily aggressive encounters for 2 weeks, during which they formed a stable dominance relationship. We also included control animals that were exposed to an empty cage each day for 2 weeks. Twenty-four hours after the final pairing or empty cage exposure, half of the subjects were socially defeated in 3, 5-min encounters, whereas the others were not socially defeated. Twenty-four hours after social defeat, animals were tested for conditioned defeat in a 5-min social interaction test with a non-aggressive intruder. We collected brains after social defeat and processed the tissue for c-Fos immunoreactivity. We found that dominants were more likely than subordinates to counter-attack the resident aggressor during social defeat, and they showed less submissive and defensive behavior at conditioned defeat testing compared with subordinates. Also, social status was associated with distinct patterns of defeat-induced neural activation in select brain regions, including the amygdala, prefrontal cortex, hypothalamus, and lateral septum. Our results indicate that social status is an important form of prior experience that predicts both initial coping style and the degree of resistance to social defeat. Further, the differences in defeat-induced neural activation suggest possible brain regions that may control resistance to conditioned defeat in dominant individuals.
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Adaptação Psicológica/fisiologia , Comportamento Animal/fisiologia , Encéfalo/fisiologia , Comportamento Social , Meio Social , Animais , Cricetinae , Imuno-Histoquímica , Masculino , Mesocricetus , Proteínas Proto-Oncogênicas c-fos/biossínteseRESUMO
BACKGROUND: Neuronal iron accumulation is thought to be relevant to the pathogenesis of Parkinson's disease (PD), although the mechanism remains elusive. We hypothesized that neuronal iron uptake may be stimulated by functional mitochondrial iron deficiency. OBJECTIVE: To determine firstly whether the mitochondrial toxin, 1-methyl-4-phenylpyridinium iodide (MPP(+)), results in upregulation of iron-import proteins and transporters of iron into the mitochondria, and secondly whether similar changes in expression are induced by toxins with different mechanisms of action. METHODS: We used quantitative PCR and Western blotting to investigate expression of the iron importers, divalent metal transporter, transferrin receptor 1 and 2 (TfR1 and TfR2) and mitoferrin-2 and the iron exporter ferroportin in differentiated SH-SY5Y cells exposed to three different toxins relevant to PD, MPP(+), paraquat (a free radical generator) and lactacystin (an inhibitor of the ubiquitin-proteasome system (UPS)). RESULTS: MPP(+) resulted in increased mRNA and protein levels of genes involved in cellular iron import and transport into the mitochondria. Similar changes occurred following exposure to paraquat, another inducer of oxidative stress. Lactacystin also resulted in increased TfR1 mRNA levels, although the other changes were not found. CONCLUSION: Our results support the hypothesis of a functional mitochondrial iron deficit driving neuronal iron uptake but also suggest that differences exist in neuronal iron handling induced by different toxins.