Encefalitis por anticuerpos anti receptor N-metil-D-aspartato ( anti-NMDAR): A propósito de un caso

La encefalitis anti receptor N-metil-D-aspartato (NMDAR) es una enfermedad autoinmune que debe sospecharse cuando un paciente se presenta con una combinación de síntomas psiquiátricos, disfunción autonómica, movimientos anormales y descompensación neurológica. La importancia de la sospecha clínica y la comprobación del diagnóstico es crucial ya que, a pesar de la gravedad del padecimiento, los pacientes a menudo mejoran luego de una larga estadía intrahospitalaria con inmunoterapia y atención multidisciplinaria. Presentamos un escolar de 11 años , febril con historia de debilidad generalizada, somnolencia, hiporexia, desorientación, hipología de miembros inferiores, que evoluciona hacia agitación psicomotora, discinesias, alteraciones de la conducta, del habla y deterioro neurológico progresivo.

The encephalitis anti NMDA receptor (N-Methyl-D-Aspartate Receptor) is an autoimmune disease, that should be suspected when a patient presents with a combination psychiatric symptoms, autonomic dysfunction, abnormal movements and neurological decompensation. The importance of clinical suspicious and verification of diagnosis is crucial because, despite the severity of the disease, patients often improve after a long hospital stay with immunotherapy and multidisciplinary care. We report a 11 years old male, afebrile with a history of generalized weakness, drowsiness, decreased appetite, disorientation, lower limb hypotonia, psychomotor agitation progressing to, dyskinesia, abnormal behavior, speech and progressive neurological deterioration.

Encefalitis por Anticuerpos contra el Receptor N-metil D-aspartato(NMDAR) en Pediatría. Reporte de caso y revisión de la literatura / Encephalitis associated with antibodies against the N-methyl-D-aspartate receptor (NMDAR) in pediatrics. Case report

La Encefalitis por Anticuerpos contra el Receptor N-metil D-aspartato (NMDAR) es un trastorno grave conuna presentación inicial puramente neuropsiquiátrica, que evoluciona hacia una encefalopatía severa, y es acompañadopor movimientos involuntarios, convulsiones e inestabilidad autonómica; el curso de la enfermedadusualmente se prolonga y necesita tratamiento inmunomodulador agresivo.Se describe el caso de un paciente de 5 años con diagnóstico de Encefalitis por Anticuerpos contra el ReceptorN-metil D-aspartato (NMDAR), manejado con tratamiento inmunomodulador, logrando así control y noprogreso de enfermedad...

Anti-NMDA receptor encephalitis is a severe disorder with a dramatic clinical presentation, often showing apurely initial neuropsychiatric phase, and evolving into a severe encephalopathy accompanied by involuntarymovements, seizures and autonomic instability; the disease course is typically prolonged and needs intensivecare treatment.We report the case of a 5-year-old child, diagnosed with Anti-NMDA receptor encephalitis with immunemodulatory therapy...

Receptores NMDA: plasticidad sináptica y supervivencia neuronal / NMDA Receptors: Synaptic Plasticity and Neuronal Survival

Un objetivo clave de las investigaciones actuales es el estudio de las redes de señalización intracelular vinculadas a la plasticidad sináptica, así como a la supervivencia y a la muerte neuronal. Haremos una revisión bibliográfica acerca de la neurotransmisión glutamatérgica, en especial de los receptores NMDA, de las variantes en la composición de sus subunidades, y de su localización sináptica o extrasináptica que nos acerca a la comprensión de los mecanismos paradigmáticos de plasticidad sináptica como la potenciación de largo plazo (LTP) y la depresión de largo plazo (LTD), relacionados con la memoria y el aprendizaje, así como con las enfermedades neurodegenerativas generadas por la excitotoxicidad. También analizaremos las diferencias y roles opuestos del factor neurotrófico derivado del cerebro (BDNF) y del pro-BDNF en la supervivencia neuronal y la apoptosis. Y en una aplicación clínica de estos conceptos, revisaremos su influencia en el desarrollo de la enfermedad de Huntington...

A key goal of current research is to study the intracellular signaling networks associated with synaptic plasticity and survival and neuronal death. We will do a bibliographic review on glutamatergic neurotransmission, especially NMDA receptors, the variations in the composition of its subunits, and its synaptic or extrasynaptic localization, bringing us closer to understanding the paradigmatic mechanisms of LTP and LTD, related with memory and learning, as well as neurodegenerative diseases generated by excitotoxicity. We will also analyze the differences and opposing roles of BDNF and pro-BDNF in neuronal survival and apoptosis. And by clinically applying these concepts, we shall review its influece in the development of Huntington's disease...

Inibição do receptor de glutamato do tipo NMDA em um modelo de hipóxia-isquemia prenatal: avaliação morfofuncional do cerebelo / Inhibition of glutamate NMDA receptor in a prenatal hipoxia-ischemia model: morphofunctional analises of cerebellum

Lesões sistêmicas peri e pré-natais alteram o desenvolvimento do SNC, levando a problemas cognitivos e motores em crianças que podem perdurar por toda a vida. Um tipo particular de lesão é a hipóxia-isquemia (HI), caracterizada pela interrupção momentânea ou permanente do fluxo sanguíneo. Um dos mecanismos propostos para as lesões decorrentes da HI é a excitotoxicidade glutamatérgica. O uso de inibidores da neurotransmissão glutamatérgica tem sido estudados em diversos modelos de HI. Neste trabalho, avaliamos os efeitos morfofuncionais da administração de um antagonista não-competitivo do receptor de glutamato NMDA sobre o desenvolvimento do cerebelo. Ratas no 18º dia de gestação foram anestesiadas, os cornos uterinos expostos e as 4 artérias uterinas obstruídas por 45 minutos (Grupo H). Animais controle tiveram os úteros expostos, sem a obstrução (Grupo S). Após a cirurgia a gestação prosseguiu. Somente animais nascidos a termo foram utilizados. Um dia após o nascimento, metade de cada ninhada foi designada para receber MK801, 0,3mg/kg/dia, (grupos SM e HM) e a outra metade recebeu solução salina (grupos SS e HS), por 5 dias. Após anestesia e perfusão-fixação com paraformaldeído 4% aos 9, 23, 30 e 60 dias pós-natais, cortes parassagitais do cerebelo foram obtidos em criótomo e submetidos à imunohistoquímica para calbindina, GFAP, GLAST, PDGFRα e MBP. A partir de 45 dias de vida, os animais foram testados em vários de testes comportamentais: labirinto em cruz elevado (LCE), campo vazado (CV), ROTAROD, teste de caminhada sobre barras (ladder test) e teste do comprimento da passada (stride length). Aos 9 dias, a espessura da árvore dendrítica era menor nos animais SM, HS/HM, demonstrando efeitos deletérios tanto do MK801 quanto da HI. Menor número de células PDGFRα+ foi observado nos animais HS/HM, sem efeitos da administração de MK801. Aos 23 dias, maior número de células PDGFRα+ foi observado nos animais HM comparado aos outros 3 grupos, indicando efeito ...

Peri and prenatal systemic lesions alter CNS development leading to motor and cognitive problems in children that might persist throughout life. A particular kind of injury, the hypoxic ischemic (HI), is characterized by a permanent or temporary blockage of blood flow. One of the proposed mechanisms downstream from a HI event is called glutamatergic excitotoxicity. The administration of glutamate inhibitors has been studied in HI models for several years. In this work, we evaluated the effects of administration of a non-competitive antagonist of glutamate receptor, NMDA, on cerebellar development and behavioral tests of HI animals. Pregnant rats in the 18th gestational day were anesthetized, the uterine horns were exposed and the four uterine arteries were clamped for 45 minutes (group H). Sham controls had the uterine horns exposed, but no arteries were clamped (group S). Gestation proceeded after surgery. Only full term animals were used. One day after birth half the animals was assigned to receive either SALINE (groups SS and HS) or MK801 (groups SM and HM). Animals were anesthetized and perfused with 4% paraformaldehyde at 9, 23, 30 and 60 days of age. Parasagittal cerebellar sections were submitted to Calbindin, GFAP, GLAST, PDGFRα and MBP immunohistochemistry. Beginning at P45 animals were subjected to a battery of behavioral tests: elevated plus maze (EPM), hole board (HB), ROTAROD, ladder test and stride length. At P9 the dendritic tree of Purkinje cells were thinner in SM, HS/HM animals, indicating that both HI and MK801 are deleterious regarding this Purkinje cell differentiation. A lower number of PDGFRα+ cells was observed in HS/HM animals, with no effects of MK801 administration. At P23 a greater number of PDGFRα+ cells was found in HM animals when compared to the other 3 groups, demonstrating a neuroprotector effect of MK801. A lower number of myelinated fibers (MBP+) was observed in HS animals at P9, and MK801 administration reverse this ...

Encefalitis asociada a anticuerpos contra los receptores NMDA: reconocimiento de un nuevo síndrome neuropsiquiátrico: [revisión] / Encephalitis associated with NMDA receptor antibodies: recognizing a novel neuropsychiatric syndrome: [review]

Los síndromes paraneoplásicos se caracterizan por la presencia de signos y síntomas que ocurren lejos del sitio del tumor o de sus metástasis. Muchos de estos síndromes son mediados por hormonas, citoquinas, u otras sustancias secretadas por células tumorales, así como por una respuesta inmune contra el tumor. La presencia de anticuerpos generados para combatir el tumor puede resultar en un síndrome neurológico si las células del sistema nervioso son afectadas. Las primeras descripciones de tales casos datan más de 20 años, cuando los anticuerpos anti-Hu y anti-Yo fueron descritos. Existe una variedad de síndromes paraneoplásicos, incluyendo cuadros neurológicos clásicos y diversos. En este artículo de revisión hemos querido enfatizar un cuadro neuropsiquiátrico que corresponde a un síndrome paraneoplásico descrito recientemente, aunque también puede ocurrir en pacientes sin presencia tumoral aparente. Se trata de la encefalitis asociada a anticuerpos contra los receptores N-metil-D-aspartato (NMDA). Nuestro interés en dicho síndrome, como especialistas en trastornos del movimiento, se basa en la presencia común de movimientos anormales en esta enfermedad. Sin embargo los pacientes afectados, la mayoría mujeres con teratoma ovárico, presentan un cuadro mixto, psiquiátrico inicialmente, seguido por epilepsia, empeoramiento de conciencia, disautonomía y distonía orofacial y truncal. Como resultado, la relevancia de la encefalitis asociada a anticuerpos contra los receptores NMDA abarca una variedad de especialidades incluyendo psiquiatría, neurología, oncología, inmunología, radiología, medicina general y cirugía.

As early as the late 1990s, a severe and potentially fatal multi-faceted disease, occurring predominantly in women, was reported in Japan. The earliest patients presented with psychosis or memory problems which rapidly progressed into numerous neurological complications which required intensive care. There were many different descriptions and labels attributed to the disease, thus delaying its classification as a paraneoplastic syndrome. In early 2007, this disease was characterized as an acute form of encephalitis-termed anti-N-methyl-D-aspartate (NMDA) encephalitis.

Detección de la subunidad NMDAR-1 del receptor N-metil-D-asparato (NMDAR) en el hipotálamo del ovino mediante el análisis de Western blot / Detection of the N-methyl-D-asparate receptor subunit-1 (NMDAR-1) in the hypothalamus of the sheep bye Western blot analysis

Los aminoácidos excitatorios (AAEs), L-glutamato y aspartato, son considerados las principales sustancias endógenas neuroactivas involucradas en la transmisión excitatoria. El receptorN-metíl-D-aspartato (NMDAR) es uno de los principales receptores de los AAEs. Este receptor estimula la secreción de la hormona luteinizante (LH) al facilitar la secreción de la hormona liberadora de las gonadotrofinas (GnRH). En este estudio se plantearon dos objetivos: Estandarizar la técnica de Western blot para identificar la subunidad-1 del NMDAR (NMDAR-1) en hipotálamo del ovino; y determinar si existe diferencia en la distribución de la NMDAR-1 en los diferentes cuadrantes hipotalámicos (cuadrantes dorsal-rostral, ventral-rostral, dorsal-caudal, y ventral-caudal) del ovino. Se utilizaron 100 µg de proteína total para identificar la NMDAR-1 en el hipotálamo ovino. Se evidenció un efecto del cuadrante o porción del hipotálamo ovino sobre la expresión proteica de la NMDAR-1. En particular, el cuadrante dorsal-rostral (31,5567 densidad óptica ± 13,0831;P<0,05) expresó más cantidad del receptor que el cuadrante ventral caudal (17,1517 densidad óptica ± 13,0831; P<0,05) y que el cuadrante ventral-rostral (16,4683 densidad óptica ±13,0831; P<0,05). Estos resultados demuestran que el receptor NMDA se expresa más en la región rostral del hipotálamo del ovino, área en la cual se encuentran distribuidos los cuerpos celulares y axones de las neuronas productoras de GnRH. Estos resultados sugieren la participación de la vía glutamatérgica en la regulación de la reproducción de los ovinos.

The excitatory amino acids (EAAs), L-glutamate and aspartate, are considered the major endogenous neuroactive substances involved in excitatory neurotransmission. The N-methyl-D-aspartate receptor (NMDAR) is one of the main excitatory amino acid receptors. Exogenous activation of the NMDAR results in the release of gonadotrophin-releasing hormone (GnRH) from the hypothalamus and subsequent release of luteinizing hormone (LH) from the anterior pituitary. The present study had two aims: to standardize the optimal amount of total protein required to identify the NMDAR subtype-1 (NMDAR-1) in the hypothalamus of the sheep; to determine whether a difference exists in the distribution of NMDAR-1 in different hypothalamic regions (dorsal-rostral, ventral-rostral, dorsal-caudal, and ventral-caudal quadrant) in male sheep. The optimal amount of total hypothalamic protein required to visualize the NMDAR-1 was 100 µg. There was an effect of quadrant on the expression of NMDAR-1 in the hypothalamus of the intact male sheep. In particular, dorsal-rostral quadrant (31.5567 optical density ± 13.0831) expressed more receptor than ventral-caudal quadrant (17.1517 optical density ± 13.0831; P<0.05) and ventral-rostral quadrant (16.4683 optical density ± 13.0831; P<0.05). These data suggest that NMDAR is more expressed in the rostral area of the hypothalamus, where the cell bodies and axons of the GnRH neurons are localized. Thus, these data allow suggest that glutamatergic pathway potentially is involved in modulating the reproductive activity in the ovine.

Amplificación del adn de la subunidad-1 del receptor n-metil-d-aspartato (nmdar-1) en el hipotálamo ovino mediante la técnica de rt-pcr / Dna amplification of the n-methyl-d-aspartate receptor subunit-1 (nmdar-1) in sheep hypothalamus by rt-pcr

El receptor N-metil-D-aspartato (NMDAR), uno de los principales receptores de los aminoácidos excitatorios, ha sido involucrado en el control de la secreción de la hormona luteinizante (LH) al facilitar la liberación de la hormona liberadora de la hormona luteinizante (LHRH). La capacidad del NMDAR para estimular la liberación de la LHRH está significativamente comprometida en animales castrados. En este estudio se plantearon tres objetivos: Primero, estandarizar las condiciones óptimas para re-amplificar el ADN de la subunidad-1 del NMDAR (NMDAR-1) en ovino. Segundo, determinar si existe diferencia en la distribución del ADN de la NMDAR-1 en los diferentes cuadrantes hipotalámicos del ovino no castrado y finalmente, determinar si las hormonas sexuales testiculares están involucradas en la expresión del NMDAR en el hipotálamo. El ADN de la NMDAR-1 procedente de cuatro cuadrantes del hipotálamo (cuadrantes dorsal-rostral, ventral-rostral, dorsal-caudal, y ventral-caudal) fue amplificado mediante la técnica de RT-PCR. Las condiciones óptimas encontradas para amplificar el ADN de la NMDAR-1 fueron 1,5 mM CIMg2, 100 nM de los oligonucleótidos iniciadores y 59°C como temperatura de hibridación. No se observó efecto del cuadrante del hipotálamo sobre la expresión del ADN de la NMDAR-1 en el hipotálamo del ovino no castrado. La castración redujo (P < 0,05) la expresión del ADN para el NMDAR-1, comparado con la de animales no castrados. Estos resultados sugieren que el NMDAR-1 se encuentra distribuido ampliamente en el hipotálamo del ovino. Además, a través de estos resultados se puede presumir que la expresión del receptor NMDA en el hipotálamo del ovino está afectada por las hormonas sexuales esteroideas.

The N-methyl-D-aspartate receptor (NMDAR), one of the excitatory amino acid receptors, has been implicated in the control of luteinizing hormone (LH) secretion through facilitation of luteinizing hormone releasing-hormone (LHRH). Interestingly, the ability of NMDAR to stimulate LHRH release is significantly compromised in castrated animals. The present study had three aims. Firstly, to standardize the optimal conditions used to amplify the DNA for NMDAR subtype-1 (NMDAR-1) in the sheep. Second, to determine whether a difference exists in the distribution of DNA for NMDAR-1 in different hypothalamic regions in intact male sheep. Finally, to determine if testicular steroid hormones are involved in NMDA receptor expression in the hypothalamus. The DNA of NMDAR-1 was amplified by RT-PCR in four quadrants of the hypothalamus (dorsal-rostral, ventral-rostral, dorsal-caudal, and ventral-caudal quadrant) of intact and castrated male sheep. The optimal conditions to amplify the DNA of NMDAR-1 were 1.5 mM MgCl2, 100 nM of primers and 59°C annealing temperature. In experiment 1, there was no effect of quadrant on the DNA expression of NMDAR-1 in the hypothalamus of the intact male sheep. Experiment 2 revealed that castration reduced (P < 0.05) the expression of DNA for NMDAR compared to that in intact males. Taken together, these data suggest that NMDAR-1 is widely expressed in the hypothalamus of male sheep. Furthermore these experiments suggest that testicular steroid hormones are involved in the regulation of NMDAR-1 expression at the DNA level, which allows understanding of its involvement in the modulation of different activities including reproduction.

A study of localization of NMDA receptor protein labelling with colloid-gold on membrane by Scanning Electron Microscopy / 解放军医学杂志

Objective To investigate the distribution rule of NMDA receptor protein localizated on neuron membrane surface. Methods After the primary culture model of forebrain cortex neuron of rat had been set up,the NR1 subunit protein molecule of NMDA receptor has been combined with primary antibody IgG,and marked by Staphylococcus protein A-colloid gold particles (SPA-G). Then the neuron was observed with Field-emission SEM,and the content of AU element was calcalated by software. Results The cluster of NMDA receptor combined with SPA-G particulates was clearly observed as some globular being distributed mainly under some niches of lipid rafts,mainly localized at originating section of dendritic protuberance of neuron membrane surface. Conclusion NMDA receptor molecule protein was distributed on the membrane surface lipid rafts of originating section of dendritic protuberance of neuron. It was in accord with the distribution rule of postsynaptic membrane on neuron. The Field-emission SEM could distinguish single NMDA receptor melocule cluster after being marked with SPA-G molecule in neuron.

The Role of Peripheral N-Methyl-D-Aspartate (NMDA) Receptors in Freund's Complete Adjuvant Induced Mechanical Hyperalgesia in Rats / 대한마취과학회지

BACKGROUND: While the effects of excitatory amino acids have been characterized in the central nervous system, relatively little is known about their possible modulation of elements responsible for hyperalgesia within peripheral tissue. The purpose of this study was to investigate the role of excitatory amino acid receptors in mechanical hyperalgesia induced by a subcutaneous injection of Freund's complete adjuvant (FCA) into the rat hind paw. METHODS: Inflammations were induced by injecting FCA on the dorsal surface of the right hind paw of rats. Effects of excitatory aminoacid agonists or antagonists on mechanical hyperalgesia were investigated by a subcutaneous injection of a drug to the inflamed paw. Mechanical hyperalgesia was expressed as percent change in paw withdrawal threshold compared to baseline value that was measured before drug injection after inflammation was induced with FCA. RESULTS: In normal rats, an intraplantar (i.pl.) injection of L-glutamate, but not of D-glutamate (3 pmol/0.1 ml each) produced a mechanical hyperalgesia in the hind paw with a lowered paw paw-withdrawal threshold to pressure. In rats that developed the mechanical hyperalgesia associated with inflammation in the hind paw following an i.pl. injection of FCA (0.15 ml), the injection of a N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 (1 pmol/0.1 ml) into the inflamed paw increased the paw pressure threshold (24.24.6% increase from baseline, P < 0.05). On the other hand, the injection of a non-NMDA receptor antagonist, 6-cyano-7-nitroqiunoxaline-2,3-dione (CNQX, 10 pmol/0.1 ml) into the inflamed paw had no effect on the FCA-induced lowering of the paw pressure threshold. CONCLUSIONS: The results suggest that NMDA, but not non-NMDA receptors play a substantial role in mediating the development of mechanical hyperalgesia induced in the inflamed paw following an i.pl. FCA injection.