RESUMO
Autism spectrum disorder (ASD) occurs in 1 in 68 births, preferentially affecting males. It encompasses a group of neurodevelopmental abnormalities characterized by impaired social interaction and communication, stereotypic behaviors and motor dysfunction. Although recent advances implicate maternal brain-reactive antibodies in a causative role in ASD, a definitive assessment of their pathogenic potential requires cloning of such antibodies. Here, we describe the isolation and characterization of monoclonal brain-reactive antibodies from blood of women with brain-reactive serology and a child with ASD. We further demonstrate that male but not female mice exposed in utero to the C6 monoclonal antibody, binding to contactin-associated protein-like 2 (Caspr2), display abnormal cortical development, decreased dendritic complexity of excitatory neurons and reduced numbers of inhibitory neurons in the hippocampus, as well as impairments in sociability, flexible learning and repetitive behavior. Anti-Caspr2 antibodies are frequent in women with brain-reactive serology and a child with ASD. Together these studies provide a methodology for obtaining monclonal brain-reactive antibodies from blood B cells, demonstrate that ASD can result from in utero exposure to maternal brain-reactive antibodies of single specificity and point toward the exciting possibility of prognostic and protective strategies.
Assuntos
Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Adulto , Animais , Anticorpos/sangue , Anticorpos/metabolismo , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/genética , Transtorno Autístico/genética , Transtorno Autístico/metabolismo , Encéfalo/metabolismo , Complemento C6 , Feminino , Hipocampo/metabolismo , Humanos , Aprendizagem , Troca Materno-Fetal , Proteínas de Membrana/sangue , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mães , Proteínas do Tecido Nervoso/sangue , Neurônios/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores Sexuais , Comportamento SocialRESUMO
BACKGROUND: Combining tDCS with robotic therapy is a new and promising form of neurorehabilitation after stroke, however the effectiveness of this approach is likely to be influenced by the relative timing of the brain stimulation and the therapy. OBJECTIVE: To measure the kinematic and neurophysiological effects of delivering tDCS before, during and after a single session of robotic motor practice (wrist extension). METHODS: We used a within-subjects repeated-measurement design in 12 chronic (>6 months) stroke survivors. Twenty minutes of anodal tDCS was delivered to the affected hemisphere before, during, or after a 20-minute session of robotic practice. Sham tDCS was also applied during motor practice. Robotic motor performance and corticomotor excitability, assessed through transcranial magnetic stimulation (TMS), were evaluated pre- and post-intervention. RESULTS: Movement speed was increased after motor training (sham tDCS) by â¼20%. Movement smoothness was improved when tDCS was delivered before motor practice (â¼15%). TDCS delivered during practice did not offer any benefit, whereas it reduced speed when delivered after practice (â¼10%). MEPs were present in â¼50% of patients at baseline; in these subjects motor practice increased corticomotor excitability to the trained muscle. CONCLUSIONS: In a cohort of stroke survivors, motor performance kinematics improved when tDCS was delivered prior to robotic training, but not when delivered during or after training. The temporal relationship between non-invasive brain stimulation and neurorehabilitation is important in determining the efficacy and outcome of this combined therapy.
Assuntos
Córtex Motor/fisiopatologia , Robótica/métodos , Reabilitação do Acidente Vascular Cerebral , Estimulação Magnética Transcraniana/métodos , Adulto , Idoso , Potencial Evocado Motor , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Fatores de TempoRESUMO
STUDY DESIGN: Case report. OBJECTIVES: To identify preserved corticomotor connection in chronic spinal cord injury (SCI) in the absence of clinically observable movement. SETTING: Rehabilitation Hospital and Medical Research Institute, NY, USA. METHODS: The motor-evoked potential (MEP) response to transcranial magnetic stimulation (TMS) was recorded using surface electromyography from the right biceps brachii, extersor carpi radialis (ECR), flexor carpi radialis (FCR) and abductor pollicis brevis (APB) muscles in a 31-year-old male traumatic SCI chronic patient-ASIA B, injury level C5. Motor power scores were additionally obtained from a clinician blinded to the results of TMS. RESULTS: TMS could consistently elicit MEPs of normal latency, phase and amplitude, in the severely affected ECR muscle but not the similarly affected FCR muscle. The response in proximal and unaffected biceps muscle was larger than the healthy subject, whereas no response was obtained in the distal APB muscle as expected. CONCLUSION: TMS can identify residual pathways not apparent from clinical assessment alone, which may have prescriptive value for rehabilitation.
Assuntos
Braço/fisiopatologia , Potencial Evocado Motor/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Adulto , Estimulação Elétrica/métodos , Humanos , Masculino , Córtex Motor/fisiopatologia , Movimento/fisiologia , Contração Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Traumatismos da Medula Espinal/terapia , Estimulação Magnética Transcraniana/métodosRESUMO
Autoimmune diseases currently affect 5-7% of the world's population; in most diseases there are circulating autoantibodies. Brain-reactive antibodies are present in approximately 2-3% of the general population but do not usually contribute to brain pathology. These antibodies penetrate brain tissue only early in development or under pathologic conditions. This restriction on their pathogenicity and the lack of correlation between serum titers and brain pathology have, no doubt, contributed to a delayed appreciation of the contribution of autoantibodies in diseases of the central nervous system. Nonetheless, it is increasingly clear that antibodies can cause damage in the brain and likely initiate or aggravate multiple neurologic conditions; brain-reactive antibodies contribute to symptomatology in autoimmune disease, infectious disease, and malignancy.
Assuntos
Autoanticorpos/metabolismo , Encéfalo/imunologia , Encéfalo/patologia , Hipóxia-Isquemia Encefálica/imunologia , Hipóxia-Isquemia Encefálica/patologia , Animais , Reações Antígeno-Anticorpo/imunologia , Encéfalo/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipóxia-Isquemia Encefálica/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologiaRESUMO
This chapter focuses on rehabilitation robotics which can be used to augment the clinician's toolbox in order to deliver meaningful restorative therapy for an aging population, as well as on advances in orthotics to augment an individual's functional abilities beyond neurorestoration potential. The interest in rehabilitation robotics and orthotics is increasing steadily with marked growth in the last 10 years. This growth is understandable in view of the increased demand for caregivers and rehabilitation services escalating apace with the graying of the population. We provide an overview on improving function in people with a weak limb due to a neurological disorder who cannot properly control it to interact with the environment (orthotics); we then focus on tools to assist the clinician in promoting rehabilitation of an individual so that s/he can interact with the environment unassisted (rehabilitation robotics). We present a few clinical results occurring immediately poststroke as well as during the chronic phase that demonstrate superior gains for the upper extremity when employing rehabilitation robotics instead of usual care. These include the landmark VA-ROBOTICS multisite, randomized clinical study which demonstrates clinical gains for chronic stroke that go beyond usual care at no additional cost.
Assuntos
Pessoas com Deficiência/reabilitação , Recuperação de Função Fisiológica , Robótica/métodos , Atividades Cotidianas , Medicina Baseada em Evidências , Humanos , Resultado do TratamentoRESUMO
Both the American Heart Association and the VA/DoD endorse upper-extremity robot-mediated rehabilitation therapy for stroke care. However, we do not know yet how to optimize therapy for a particular patient's needs. Here, we explore whether we must train patients for each functional task that they must perform during their activities of daily living or alternatively capacitate patients to perform a class of tasks and have therapists assist them later in translating the observed gains into activities of daily living. The former implies that motor adaptation is a better model for motor recovery. The latter implies that motor learning (which allows for generalization) is a better model for motor recovery. We quantified trained and untrained movements performed by 158 recovering stroke patients via 13 metrics, including movement smoothness and submovements. Improvements were observed both in trained and untrained movements suggesting that generalization occurred. Our findings suggest that, as motor recovery progresses, an internal representation of the task is rebuilt by the brain in a process that better resembles motor learning than motor adaptation. Our findings highlight possible improvements for therapeutic algorithms design, suggesting sparse-activity-set training should suffice over exhaustive sets of task specific training.
Assuntos
Adaptação Fisiológica/fisiologia , Aprendizagem/fisiologia , Destreza Motora/fisiologia , Recuperação de Função Fisiológica/fisiologia , Robótica , Reabilitação do Acidente Vascular Cerebral , Atividades Cotidianas , Idoso , Algoritmos , Fenômenos Biomecânicos , Doença Crônica , Terapia por Exercício , Feminino , Generalização Psicológica , Humanos , Masculino , Pessoa de Meia-Idade , Movimento/fisiologiaRESUMO
Systemic lupus erythematosus (SLE) is characterized by the presence of autoantibodies that can mediate tissue damage in multiple organs. The underlying aetiology of SLE autoantibodies remains unknown, and treatments aimed at eliminating B cells, or limiting their function, have demonstrated limited therapeutic benefit. Thus, the current therapies for SLE are based on the concept of nonspecific immunosuppression and consist of nonsteroidal anti-inflammatory drugs (NSAIDS), corticosteroids, anti-malarials and cytotoxic drugs, all of which have serious adverse side effects including organ damage. The major auto-specificity in SLE is double-stranded (ds) DNA. Many anti-dsDNA antibodies cross-react with non-DNA antigens that may be the direct targets for their pathogenic activity. Studying anti-dsDNA antibodies present in SLE patients and in animal models of lupus, we have identified a subset of anti-dsDNA antibodies which is pathogenic in the brain as well as in the kidney. We have recently demonstrated that specific peptides, or small molecules, can protect target organs from antibody-mediated damage. Thus, it might be possible to treat the aspects of autoimmune disease without inducing major immunosuppression and ensuing infectious complications.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/terapia , Lúpus Eritematoso Sistêmico/terapia , Animais , Anticorpos Antinucleares/uso terapêutico , Doenças Autoimunes/imunologia , DNA/imunologia , Modelos Animais de Doenças , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Camundongos , Receptores de N-Metil-D-Aspartato/imunologiaRESUMO
PURPOSE: Anodal transcranial direct current stimulation (tDCS) can transiently increase corticomotor excitability of intrinsic hand muscles and improve upper limb function in patients with chronic stroke. As a preliminary study, we tested whether increased corticomotor excitability would be similarly observed in muscles acting about the wrist, and remain present during robotic training involving active wrist movements, in six chronic stroke patients with residual motor deficit. METHODS: Transcranial magnetic stimulation (TMS) generated motor evoked potentials (MEP) in the flexor carpi radialis (FCR) and provided a measure of corticomotor excitability and short-interval cortical inhibition (SICI) before and immediately after a period of tDCS (1 mA, 20 min, anode and TMS applied to the lesioned hemisphere), and robotic wrist training (1hr). RESULTS: Following tDCS, the same TMS current strength evoked an increased MEP amplitude (mean 168 +/- 22%SEM; p < 0.05), that remained increased after robot training (166 +/- 23%; p < 0.05). Conditioned MEPs were of significantly lower amplitude relative to unconditioned MEPs prior to tDCS (62 +/- 6%, p < 0.05), but not after tDCS (89 +/- 14%, p = 0.40), or robot training (91 +/- 8%, p = 0.28), suggesting that the increased corticomotor excitability is associated with reduced intracortical inhibition. CONCLUSION: The persistence of these effects after robotic motor training, indicates that a motor learning and retraining program can co-exist with tDCS-induced changes in cortical motor excitability, and supports the concept of combining brain stimulation with physical therapy to promote recovery after brain injury.
Assuntos
Estimulação Elétrica/métodos , Potencial Evocado Motor/fisiologia , Antebraço/fisiologia , Robótica/métodos , Reabilitação do Acidente Vascular Cerebral , Punho/inervação , Idoso , Idoso de 80 Anos ou mais , Doença Crônica , Estimulação Elétrica/instrumentação , Feminino , Lateralidade Funcional , Humanos , Masculino , Fatores de Tempo , Estimulação Magnética Transcraniana/métodosRESUMO
Synergies are thought to be the building blocks of vertebrate movements. The inability to execute synergies in properly timed and graded fashion precludes adequate functional motor performance. In humans with stroke, abnormal synergies are a sign of persistent neurological deficit and result in loss of independent joint control, which disrupts the kinematics of voluntary movements. This study aimed at characterizing training-related changes in synergies apparent from movement kinematics and, specifically, at assessing: 1) the extent to which they characterize recovery and 2) whether they follow a pattern of augmentation of existing abnormal synergies or, conversely, are characterized by a process of extinction of the abnormal synergies. We used a robotic therapy device to train and analyze paretic arm movements of 117 persons with chronic stroke. In a task for which they received no training, subjects were better able to draw circles by discharge. Comparison with performance at admission on kinematic robot-derived metrics showed that subjects were able to execute shoulder and elbow joint movements with significantly greater independence or, using the clinical description, with more isolated control. We argue that the changes we observed in the proposed metrics reflect changes in synergies. We show that they capture a significant portion of the recovery process, as measured by the clinical Fugl-Meyer scale. A process of "tuning" or augmentation of existing abnormal synergies, not extinction of the abnormal synergies, appears to underlie recovery.
Assuntos
Terapia por Exercício/métodos , Movimento/fisiologia , Desempenho Psicomotor/fisiologia , Reabilitação do Acidente Vascular Cerebral , Acidente Vascular Cerebral/fisiopatologia , Braço/fisiologia , Fenômenos Biomecânicos , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica/fisiologia , Características de Residência , RobóticaRESUMO
Although cells of the innate immune response have a variety of pattern recognition receptors that are triggered by blood classes of markers, a critical feature of the adaptive immune response is antigenic specificity. Yet it is becoming increasingly clear that the specificity of lymphocyte receptors admits of some laxity. Cross-reactivity may, in fact, be necessary for lymphocyte survival as antigen receptor signaling maintains cellular viability in the absence of antigen activation. Studies of molecular mimicry have revealed many instances in which antibodies to microbial antigens bind also to self-antigens; in some cases, this cross-reactivity has pathogenic potential. In this chapter, we describe cross-reactivity between two self-antigens, DNA and NMDA receptors, and how antibodies with specificity for DNA in patients with splenic lupus may cause central nervous system damage by virtue of binding also to neuronal receptors. This example serves as a reminder that cross-reactivity may exist among self-antigens as well as between foreign and self-antigens.
Assuntos
Anticorpos Antinucleares/metabolismo , Autoantígenos/metabolismo , Mimetismo Molecular/imunologia , Animais , Autoimunidade , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/imunologia , Sistema Nervoso Central/imunologia , Reações Cruzadas , Epinefrina/farmacologia , Humanos , Lipopolissacarídeos/toxicidade , Vasculite Associada ao Lúpus do Sistema Nervoso Central/etiologia , Vasculite Associada ao Lúpus do Sistema Nervoso Central/imunologia , Camundongos , Receptores de N-Metil-D-Aspartato/imunologiaRESUMO
The inflammatory response accompanies and exacerbates the developing injury after cerebral ischemia. Ibuprofen, a non-steroidal anti-inflammatory drug, has been shown to attenuate injuries in animal models of various neurological diseases. In the present study, we investigated ibuprofen's neuroprotective effects in rats exposed to transient forebrain ischemia and in cultures exposed to oxygen glucose deprivation (OGD). Rats treated with ibuprofen after transient forebrain ischemia displayed long-lasting protection of CA1 hippocampal neurons. There were selective increases in interleukin-1 receptor antagonist gene and protein expression in ibuprofen-treated OGD microglia. Furthermore, treatment with ibuprofen in neuron/microglia co-cultures increased the number of surviving HC2S2 neurons against OGD whereas IL-1ra neutralizing antibody reversed the ibuprofen-induced neuroprotection. The data indicate that ibuprofen-induced IL-1ra secretion is involved in neuroprotection against ischemic conditions.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Isquemia Encefálica/prevenção & controle , Ibuprofeno/uso terapêutico , Neurônios/efeitos dos fármacos , Sialoglicoproteínas/metabolismo , Análise de Variância , Animais , Western Blotting/métodos , Isquemia Encefálica/complicações , Contagem de Células/métodos , Morte Celular/efeitos dos fármacos , Linhagem Celular , Técnicas de Cocultura/métodos , Relação Dose-Resposta a Droga , Glucose/deficiência , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipóxia , Imuno-Histoquímica/métodos , Proteína Antagonista do Receptor de Interleucina 1 , Masculino , Camundongos , Microglia/efeitos dos fármacos , Neurônios/química , Neurônios/citologia , Ratos , Ratos Wistar , Sialoglicoproteínas/farmacologia , Regulação para Cima/efeitos dos fármacosRESUMO
In response to cerebral ischemia, neurons activate survival/repair pathways in addition to death cascades. Activation of cyclic AMP-response-element-binding protein (CREB) is linked to neuroprotection in experimental animal models of stroke. However, a role of the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MAPK/ERK or MEK), an upstream kinase for CREB, and its relation to CREB phosphorylation in neuroprotection in cerebral ischemia has not been delineated. Previously, we reported that N-acetyl-O-methyldopamine (NAMDA) significantly protected CA1 neurons after transient forebrain ischemia [J Neurosci 19 (1999b) 87.8]. The current study is to investigate whether NAMDA-induced neuroprotection occurs via the activation of ERK and its downstream effector, CREB. NAMDA induced ERK1/2 and CREB phosphorylation with increased survival of HC2S2 hippocampal neurons subjected to oxygen-glucose deprivation. These effects were reversed by U0126, a MEK kinase inhibitor. Similarly, animals treated with NAMDA following ischemia showed increased ERK and CREB phosphorylation in the CA1 subregion of the hippocampus during early reperfusion period with increased number of surviving neurons examined 7 days following ischemia. The NAMDA-induced neuroprotection was abolished by U0126 administered shortly after reperfusion. The results showed that the ERK-CREB signaling pathway might be involved in NAMDA-induced neuroprotection following transient global ischemia and imply that the activation of the pathway in neurons may be an effective therapeutic strategy to treat stroke or other neurological syndromes.
Assuntos
Dopamina/análogos & derivados , Dopamina/farmacologia , Hipocampo/enzimologia , Ataque Isquêmico Transitório/enzimologia , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Neurônios/enzimologia , Animais , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dopamina/uso terapêutico , Inibidores Enzimáticos/farmacologia , Hipocampo/efeitos dos fármacos , Ataque Isquêmico Transitório/tratamento farmacológico , Ataque Isquêmico Transitório/prevenção & controle , Masculino , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Thirty patients with chronic stroke received 6 weeks of sensorimotor robotic training in a pilot study that targeted motor function of the affected shoulder and elbow. The impairment and disability scores were stable during a 2-month observation/measurement period, improved significantly by program completion, and remained robust in the 3-month follow-up. Task-specific motor training attenuated a chronic neurologic deficit well beyond the expected period for improvement after stroke.
Assuntos
Transtornos das Habilidades Motoras/terapia , Robótica , Acidente Vascular Cerebral/terapia , Adulto , Idoso , Braço/fisiologia , Doença Crônica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos das Habilidades Motoras/diagnóstico , Projetos Piloto , Acidente Vascular Cerebral/diagnóstico , Resultado do TratamentoRESUMO
Dopaminergic neurons in the substantia nigra pars compacta undergo apoptosis after transection of the medial forebrain bundle. We have assessed the temporal and sequential activities of microglia in these events by examining the complement-3 (OX-42), major histocompatibility complex class II antigen presentation (OX-6) and phagocytic activity (ED1), and correlating these indicators with dopaminergic neuronal loss. Microglia in the ipsilateral substantia nigra pars reticulata evinced activation morphology at 12 h postaxotomy. Phagocytic microglia apposed dying dopaminergic neurons in the pars compacta starting at 3 days postlesion; their number increased through 14 days and slowly decreased. Nuclear chromatin condensation and significant loss of tyrosine hydroxylase-positive dopaminergic neurons occurred around 7 days postlesion. In contrast to microglial expression of interleukin-1beta and inducible nitric oxide synthase at the axotomy site, nigral microglia were interleukin-1beta and inducible nitric oxide synthase-negative. Consistently, RNase protection assays showed that interleukin-1beta and inducible nitric oxide synthase transcripts in nigra were equivocal. The present data support the idea that phagocytosis of axotomized neurons by activated microglia is not limited to dead neurons but includes dying neurons probably without cytotoxic effects of inflammatory substances, such as interleukin-1beta or nitric oxide.
Assuntos
Feixe Prosencefálico Mediano/fisiologia , Microglia/metabolismo , Substância Negra/metabolismo , Animais , Apoptose/fisiologia , Axotomia , Citocinas/metabolismo , Masculino , Microglia/patologia , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo II , Ratos , Ratos Wistar , Substância Negra/patologia , Fatores de Tempo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
There is no "magic bullet" in rehabilitation. In the absence of direct neural transplants, neurological rehabilitation is an arduous process. We have pioneered the clinical application of robotics in stroke rehabilitation and have shown evidence of the positive impact of targeted exercise on stroke recovery. In this article, we will review results obtained in the initial clinical trials with 96 stroke patients at the Burke Rehabilitation Hospital. We will provide evidence that robot-aided training enhances recovery, that this enhanced recovery is sustained in the long term, and that this recovery is not due to a general physiological improvement--in fact, it appears to be limb and muscle group specific. An evidence-based approach must now segue into a more scientific approach to stroke rehabilitation. Given the length of the required protocols and patients' variability and limited census, the practical limitations of the evidence-based approach are self-evident and extend trials for years. Each patient and lesion is unique in stroke rehabilitation, so there is no reason to believe that a "one-size-fits-all" optimal treatment exists. To optimize therapy for individual patients, we need science-based models. In this article, we will summarize the scientific tools and models that we are investigating and present some of the results to date.
RESUMO
Stroke is the leading cause of disability, despite continued advances in prevention and treatment techniques based on novel delivery of new fibrinolytic drugs. Improved medical treatment of the complications caused by acute stroke has contributed to decreased mortality, but 90% of the survivors have significant neurological deficits. Reducing the degree of permanent disability remains the goal of poststroke neuro-rehabilitation programs, and new approaches to impairment reduction through managing sensorimotor experience may contribute further to altering disability. Recent reports from a number of laboratories using enhanced sensorimotor training protocols, particularly those with robotic devices, have indicated modest success in reducing impairment and increasing motor power in the exercised limb of patients with stroke when compared with control individuals. Whether arming the therapist with new tools, especially robotic devices, to treat impairment is a realistic approach to modern interdisciplinary rehabilitation raises questions regarding the added value of impairment reduction, and under what conditions should scientific and clinical development of robotic studies continue.
Assuntos
Modalidades de Fisioterapia/instrumentação , Desempenho Psicomotor , Robótica/instrumentação , Reabilitação do Acidente Vascular Cerebral , Terapia Assistida por Computador/instrumentação , Avaliação da Deficiência , Transtornos Neurológicos da Marcha , Humanos , Avaliação de Processos e Resultados em Cuidados de SaúdeRESUMO
In systemic lupus erythematosus, antibodies against double-stranded DNA are a major contributor to renal disease. We have previously demonstrated that the pentapeptide Asp/Glu-Trp-Asp/Glu-Tyr-Ser/Gly is a molecular mimic of double-stranded DNA. This sequence is also present in the extracellular domain of murine and human NMDA (N-methyl-D-aspartate) receptor subunits NR2a and NR2b. Here we show that the NR2 receptor is recognized by both murine and human anti-DNA antibodies. Moreover, anti-DNA antibodies with this cross-reactivity mediate apoptotic death of neurons in vivo and in vitro. Finally, we show that the cerebrospinal fluid of a patient with systemic lupus erythematosus contains these antibodies and also mediates neuronal death via an apoptotic pathway. These observations indicate that lupus antibodies cross-react with DNA and NMDA receptors, gain access to cerebrospinal fluid and may mediate non-thrombotic and non-vasculitic abnormalities of the central nervous system.
Assuntos
Anticorpos Antinucleares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Animais , Anticorpos Antinucleares/líquido cefalorraquidiano , Apoptose , Células Cultivadas , Reações Cruzadas , Humanos , Técnicas In Vitro , Lúpus Eritematoso Sistêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/imunologia , Neurônios/patologiaRESUMO
The role of c-Fos in neurodegeneration or neuroprotection after cerebral ischemia is controversial. To investigate whether early c-Fos induction after ischemia is associated with neuroprotection, rats were subjected to 10 minutes of transient forebrain ischemia and c-Fos expression was examined. Resistant dentate granule cells and neurons in CA2-4 displayed more robust immunoreactivity than vulnerable neurons in the CA1 region of hippocampus during early hours of reperfusion. By 6 hours after reperfusion, c-Fos immunoreactivity was greatly diminished in all areas of the hippocampus. Administration of N-acetyl-O-methyldopamine (NAMDA), a compound previously shown to protect CA1 neurons against ischemia, increased c-Fos immunoreactivity in the CA1 vulnerable region at 6 hours after ischemia and protected SK-N-BE(2)C neurons from oxygen glucose deprivation. Further in vitro study showed that NAMDA potentiated phorbol-12 myristate-13 acetate (PMA)-induced c-Fos expression, AP1 binding activity, and late gene expression determined by chloramphenicol acetyltransferase (CAT) activity from AP1 containing tyrosine hydroxylase promoter-CAT fusion gene in SK-N-BE(2)C neurons. In vivo and in vitro results showed that a neuroprotectant, NAMDA, in concert with another stimulus (for example, ischemia or PMA) up-regulates c-Fos expression and suggested that the early rise of NAMDA-induced c-Fos expression in vulnerable CA1 neurons may account for neuroprotection by means of up-regulating late gene expression for survival.
Assuntos
Ataque Isquêmico Transitório/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Traumatismo por Reperfusão/prevenção & controle , Animais , Western Blotting , Cloranfenicol O-Acetiltransferase/genética , Dopamina/análogos & derivados , Dopamina/farmacologia , Sinergismo Farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/administração & dosagem , Hipocampo/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Neuroblastoma , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Oxigênio/administração & dosagem , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-fos/análise , Proteínas Proto-Oncogênicas c-fos/genética , Ratos , Ratos Wistar , Proteínas Recombinantes de Fusão/metabolismo , Acetato de Tetradecanoilforbol/farmacologia , Fator de Transcrição AP-1/metabolismo , Células Tumorais Cultivadas , Tirosina 3-Mono-Oxigenase/genéticaRESUMO
OBJECTIVE: This study tests three hypotheses relevant for the efficient use of rehabilitation services after stroke: (a) the severity of initial motor impairment after stroke predicts discharge motor impairment and self-care mobility scores; (b) identification of those unlikely to show improvement in motor impairment can focus rehabilitzation efforts on use of compensatory techniques and assist devices; and (c) improvement in self-care mobility scores without change in motor impairment, balance, or cognition is a quantitative estimate of the value of teaching compensatory techniques and use of assist devices. METHODS: We studied 171 sequential patients previously independent in the community who were admitted for inpatient rehabilitation within 17 +/- 12 SD days of an initial, unilateral, hemispheric, ischemic stroke. Impairment was assessed using the Fugl-Meyer upper limb motor (ULM), lower limb motor (LLM), and upper plus lower limb total motor (TM) subscores. Disability was assessed using the Functional Independence Measure (FIM), FIM self-care (FIMS), FIM mobility (FIMM), and FIM self-care plus FIM mobility (FIMSM) subscores. Spearman correlation coefficients tested strength of association between dependent and independent variables, stepwise linear regression tested the effects of clinically relevant co-variables, and positive and negative predictive values (PPV, NPV) assessed the clinical relevance of outcome-prediction models. RESULTS: The highest correlations observed were between admission TM scores and the following discharge scores: TM (R = 0.92; p < 0.01), ULM (R = 0.91; p < 0.01), LLM (R = 0.82; p < 0.01), FIMSM (R = 0.67; p < 0.01), FIMM (R = 0.67; p < 0.001), FIM (R = 0.58; p < 0.0001). An admission TM score in the lowest quartile had a PPV of 0.74 for a discharge ULM score in the lowest quartile. An admission TM score in the highest quartile had a PPV of 0.86 for a discharge ULM score in the highest quartile. Similar but weaker PPVs were seen for admission TM scores and discharge LLM scores. Patients without significant change in TM scores (< or = 2 points) had a 17 +/- 9 SD improvement in FIMSM scores. CONCLUSIONS: Admission motor impairment scores (a) predict discharge impairment and activities of daily living mobility functional outcome; and (b) guide treatment toward improving motor impairment versus use of compensatory techniques and assistive devices. The use of compensatory techniques and assistive devices, without change in motor impairment, is associated with a 17 +/- 9 SD improvement in FIMSM score.