Corticosterone induced D-serine release deficit play an important role in long-term potentiation impairment by corticosterone in perforant path-dentate gyrus pathway / 中国药理学与毒理学杂志

OBJECTIVE Previous studies showed that over activation of NMDA receptors may be a crucial cause of long-term potentiation (LTP) and cognitive impairment induced by stress or corticosterone. However, other studies showed that the function of NMDA receptors is insufficient since the NMDA receptors co-agonist D-serine could improve stress-induced cognitive impairment. The purpose of this study is to clarify whether over activation of NMDA receptors or hypofunction of NMDA receptors is involved in hippocampal impairment of LTP by corticosterone and the underlying mechanisms. METHODS Cort was injected subcutaneously 1 h before the high-frequency stimulation (HFS) to induce LTP impairment. NMDA receptor antagonists and agonists were administrated by icv. RESULTS Hippocampal LTP and object location recognition memory were impaired in corticosterone-treated mice. Corticosterone increased the gluta?mate level in hippocampal tissues, neither NMDA receptors antagonist nor its subtype antagonists alleviated impairment of LTP, while enhancing the function of NMDA receptors by D-serine did alleviate impairment of LTP by corticosterone, suggesting that hypofunction of NMDA receptors might be one of the main reasons for impairment of LTP by corticoste?rone. Further results showed that the level of D-serine and its precursor L-serine did not change. D-serine release-related protein Na+-independent alanine-serine-cysteine transporter-1 (ASC-1) in the cell membrane was decreased and increas?ing D-serine release by the selective activator of ASC-1 antiporter activity alleviated impairment of LTP by corticoste?rone. CONCLUSION Taken together, this study demonstrates that hypofunction of NMDA receptors may be involved in impairment of LTP by corticosterone and reduced D-serine release may be an important reason for its hypofunction, which is an important complement to existing mechanisms of corticosterone-induced LTP and cognitive impairment.

Childhood Onset of Anti-N-Methyl-D-Aspartate Receptor Encephalitis Without Teratoma Masquerading as a Psychotic Disorder

Many neurologic disorders manifest as psychiatric symptoms. Anti-N-Methyl-D-Aspartate (NMDA) receptor encephalitis is an autoimmune disease of the brain characterized by numerous neurological and psychiatric features. Despite being rare, its prevalence is rapidly increasing and early management is critical in ensuring successful and sustainable recovery. Therefore, the illness should be considered as a differential diagnosis when clinically assessing patients. This report presents a case of a female child who was hospitalized for acute psychiatric manifestations, which was later confirmed as anti-NMDA receptor encephalitis. She recovered relatively successfully after combined neurological and psychiatric treatment. This report provides information on the clinical course of early onset anti-NMDA receptor encephalitis, including treatment strategy and prognosis.

Protective Effect and Mechanism of Extracts from Ginseng Radix et Rhizoma,Anemarrhenae Rhizoma and Paeoniae Radix Rubra on Hippocampal Neurons in Rats with Vascular Dementia / 中国实验方剂学杂志

Objective: To observe the effect of extracts from Ginseng Radix et Rhizoma,Anemarrhenae Rhizoma and Paeoniae Radix Rubra on N-methyl-D-aspartate receptors(NMDAR1) in hippocampal neurons in rats with vascular dementia and investigate its possible mechanism. Method: The 60 SPF male rats were randomly divided into normal group, sham-operated group,model group, traditional Chinese medicine group(0.20 g·kg-1)and memantine group(2.1 mg·kg-1),with 12 rats in each group. The model was established by repeated ischemia-reperfusion combined with intraperitoneal injection of sodium nitroprusside. After modelling, normal group, sham-operated group and model group were dosed the similar volume of normal saline once a day for 14 days. The learning and memory capacity was assessed by Morris water maze; pathologic change in the CA1 district of hippocampus was assessed by hematoxylin-eosin (HE) staining, and the expression level of NMDAR1 in hippocampal neuron membrane protein was detected by Western blot and immunohistochemistry(IHC),the NMDAR1 mRNA in hippocampal tissue was detected by Real-time PCR. Result:Compared with normal and sham-operated group, the latency period was prolonged in model group(PPPPPPPPConclusion:The extracts from Ginseng Radix et Rhizoma,Anemarrhenae Rhizoma and Paeoniae Radix Rubra can improve the learning and memory capacity of rats with vascular dementia, and alleviate the injury in CA1 district of hippocampus. The mechanism may be related to the down-regulation of NMDAR1 expression in hippocampal neurons.

NMDA Receptor Antagonist MK801 Protects Against 1-Bromopropane-Induced Cognitive Dysfunction / 神经科学通报·英文版

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.

Encefalitis por anticuerpos contra receptores de N-metil-D-aspartato y síndrome de DRESS secundario a fenitoína: Reporte de un caso / Encephalitis by anti-N-Methyl-D-Aspartate receptor antibodies and DRESS syndrome secondary to phenytoin: A case report

La encefalitis debida a anticuerpos contra receptores N-metil-D-aspartato (NMDA)es una entidad potencialmente tratable, caracterizada por síntomas neuropsiquiátricos que incluyen crisis epilépticas, alteración de conciencia, catatonía y trastornos autonómicos, y desencadenada por una respuesta inmunológica mediada por antígenos. A su vez, el síndrome DRESS (sigla en inglés de Reacción a drogas con eosinofília y síntomas sistémicos) es un cuadro de hipersensibilidad retardada mediada por células, frecuentemente asociada a fármacos antiepilépticos aromáticos. Se presenta el caso de una paciente joven que debutó con crisis epilépticas inicialmente fármaco-sensibles, desarrolló luego el síndrome de DRESS secundario a fenitoína. Cursó posteriormente con trastornos de memoria y lenguaje, alteraciones conductuales y estado catatónico y presentó anticuerpos contra receptores NMDA en el líquido cefalorraquídeo. Ambas entidades respondieron a inmunoterapia con corticoides, lo cual contribuiría a explicar una asociación fisiopatogénica entre estas dos entidades inmunomediadas.

N-Methyl-D-Aspartate receptor encephalitis is a potentially treatable entity characterized by neuropsychiatric symptoms including epileptic seizures, disruption of consciousness, catatonia, and autonomic disorders, and triggered by an immunological response mediated by an antigen. In turn, the DRESS syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms) is a delayed cell-mediated hypersensitivity reaction, frequently associated with antiepileptic aromatic drugs. The case is presented of a young patient who debuted with epileptic seizures initially drug-sensitive, developedthen DRESS syndrome secondary to the use of phenytoin, and later presented disorders of memory and language, behavioral alterations and catatonic state, and presented anti- NMDA receptor antibodies in CSF. Both entities responded to corticoid immuno-therapy, which could contribute to explain a pathogenic association between these two immunomediated entities.

A single fraction from Uncaria sinensis exerts neuroprotective effects against glutamate-induced neurotoxicity in primary cultured cortical neurons / 대한해부학회지

We identified a neuroprotective single fraction among 62 ones of hexane extract from Uncaria sinensis (JGH43IA) and investigated its effects and mechanisms in primary cortical neurons. Pretreatment with JGH43IA showed a significantly increase cell viability in a dose-dependent manner with a decrease in the lactate dehydrogenase release. When we performed morphological assay and flow cytometry to determination of the type of cell death, pretreatment with JGH43IA showed a significant reduction of glutamate-induced apoptotic cell death. Then we explored the downstream signaling pathways of N-methyl-D-aspartate receptor (NMDAR) with calpain activation to elucidate possible pathways of neuroprotection by JGH43IA. Pretreatment with JGH43IA exhibited a significant attenuation of NMDAR GluN2B subunit activation and a decrease in active form of calpain 1 leading to subsequent cleavage of striatal-enriched protein tyrosine phosphatase (STEP). In addition, pretreatment with JGH43IA showed a marked increase of cAMP responsive element binding protein. These results suggest that JGH43IA may have neuroprotective effects through down-regulation of NMDAR GluN2B subunit and calpain 1 activation, and subsequent alleviation of STEP cleavage. This single fraction from U. sinensis might be a useful therapeutic agent for brain disorder associated with glutamate injury.

Antiallodynic effects of vitamin C and vitamin E in chronic post-ischemia pain rat model / 대한마취과학회지

BACKGROUND: Recent research has shown that reactive oxygen species (ROS) play a significant role in the development and persistence of neuropathic pain through central sensitization via N-methyl-D-aspartate (NMDA) receptor activation. In the present study, we examined whether the intraperitoneal administration of vitamins C and E alone or together could alleviate mechanical allodynia in a chronic post-ischemia pain (CPIP) rat model. METHODS: Vitamins C and E were administered intraperitoneally to 48 male Sprague Dawley rats once per day for 3 days before hindpaw ischemia-reperfusion (I/R) injury was induced. On the third day, the CPIP rat model was produced by inducing ischemia in the left hindpaw by applying an O-ring for 3 h, followed by reperfusion. Three days after reperfusion, hindpaw mechanical allodynia was assessed by measuring the withdrawal response to von Frey filament stimulation. The rats were sacrificed immediately after behavioral testing to determine the phosphorylated NMDA receptor subunit 1 (pNR1) and extracellular-signal-regulated kinases (pERK) levels in the spinal cord. RESULTS: When the antioxidant vitamins C and E were administered intraperitoneally to CPIP rats, I/R injury-induced mechanical allodynia was attenuated, and pNR1 and pERK levels were decreased in the rat spinal cord. Additionally, the co-administration of both vitamins had an increased antiallodynic effect. CONCLUSIONS: The reduced phosphorylated NR1 and ERK levels indicate that vitamins C and E inhibit the modulation of spinal cord neuropathic pain processing. Co-administration of vitamins C and E had a greater antiallodynic effect.