Modulatory effects of aluminum, calcium, lithium, magnesium, and zinc ions on [ H]MK-801 binding in human cerebral cortex

The independent and combined effects of Ca²⁺, Mg²⁺, Zn²⁺, Al³⁺ and Li⁺ on [ ³H]MK-801 binding in human cerebral cortical membranes were studied to further characterize the modulatory effects of metal ions on the N-methyl-d-aspartate (NMDA) receptor-ionophore. Glycine, in the presence of glutamate, significantly intensified the Mg²⁺ inhibition of [ ³H]MK-801 binding whereas it masked the Ca²⁺ enhancement and slightly diminished the Zn²⁺ inhibition. Both Ca²⁺ and Mg²⁺ reduced the Zn²⁺ inhibitory potency. Aluminum demonstrated a potent, relatively glycine-insensitive inhibition of [ ³H]MK-801 binding as an amorphous Al(OH)₃ polymer rather than as the free ion. Cationic modulation of the NMDA receptor-ionophore appears to be regulated at multiple sites which have significant allosteric interactions.     

正确认识自身免疫性癫痫与自身免疫性脑炎的关系

自身免疫性癫痫与自身免疫性脑炎均是近年来随着神经免疫学发展而提出的临床新概念。对于伴有癫痫样发作、抗神经元抗体阳性的患者,诊断为自身免疫性脑炎还是自身免疫性癫痫,目前还存在争议和误区。由于二者存在部分共同的抗神经元抗体,且临床表现有一定重叠性,如癫痫的耐药性、合并认知功能损害等,常被临床所混淆,造成了不必要的过度抗癫痫治疗。笔者从二者临床概念、流行病学、发病机制及相关危险因素、临床表现、辅助检查、治疗和预后对二者区别和联系进行了释义。     

论自身免疫性脑炎责任抗体的致病性

自身免疫性脑炎是一种中枢神经系统自身免疫性疾病,大量新抗体的发现扩增其临床疾病谱,但也为临床表型的精准识别带来一定困难.责任抗体系指同一例患者病程中与一个或多个临床表型有对应因果关系的致病性抗体,这一概念的提出,在自身抗体与临床表型之间建立联系,体现出现代精准医学的理念.明确责任抗体的致病性是理解抗体-临床表型因果关系...     

基于“责任抗体”概念的自身免疫性脑炎诊断与治疗进展

自身免疫性脑炎是神经系统免疫性疾病的重要组成之一,存在靶向神经元表面蛋白、离子通道或突触表面受体的自身抗体,自身抗体检测对疾病的诊断、治疗及预后评估具有重要意义。确定责任抗体是解决同一例患者多种自身抗体共存的重要方法,本文基于新近提出的责任抗体概念对自身免疫性脑炎诊断与治疗进展进行综述。     

Distribution of the N-methyl-d-aspartate glutamate receptor subunit NR2A in control and amyotrophic lateral sclerosis spinal cord

The distribution of the different glutamate receptor subunits in human spinal cord has yet to be fully elucidated. The aim of this study was to examine the distribution of the N-methyl-d-aspartate (NMDA) glutamate receptor modulatory subunit NR2A, in control human spinal cord and to examine in parallel the expression of the mRNA in amyotrophic lateral sclerosis (ALS). The aetiology of ALS is poorly understood, although abnormalities in glutamate and glycine transport have been reported as well as alterations in NMDA receptors including the NRl subunit; suggesting a role for glutamate in the disease process. We have used the technique of in situ hybridisation to localise this receptor subunit to the laminae of human spinal cord and have found that it shows a widespread distribution similar to that previously reported for the universal NMDA receptor subunit NR1. Quantitation of mRNA expression in control and ALS cases showed a significant widespread loss of NR2A from both dorsal and ventral horns with losses of 55% and 78%, respectively. in ALS as compared to control, These results were substantiated by analysis of spinal cord homogenates, which showed a significant total decrease of 50% in ALS spinal cord as compared to control.     

Effects of reduced magnesium on hippocampal synchrony

Spontaneous, synchronous burst discharges originating in the CA2-CA3 region of guinea pig hippocampal slices occur when the concentration of magnesium in the perfusate is reduced below 250 microM. The burst frequency is greater than that seen with other convulsants and afterdischarge is common. Cyclic periods of bursting resembling ictal discharges occur spontaneously in some slices and with repetitive stimulation (0.5-2 Hz) in most slices. The spontaneous bursts are blocked by 2-APV suggesting the involvement of NMDA receptors in their generation.     

合并多种抗体阳性自身免疫性脑炎临床分析

目的总结自身免疫性脑炎合并多种抗神经元抗体阳性患者的临床特点及意义。方法回顾性分析郑州大学第一附属医院2015-01-2019-05确诊的7例合并多种抗神经元抗体阳性自身免疫性脑炎患者的临床表现、实验影像学检查及治疗效果,并进行相关文献复习。结果255例自身免疫性脑炎患者仅出现7例合并多抗体阳性患者,其中4例抗NMDAR抗体阳性患者分别合并抗LGI1抗体、抗-Ma2、抗-Yo抗体阳性,2例抗GABABR脑炎分别合并抗Hu、抗amphiphsin阳性,1例抗LGI1脑炎合并抗Hu阳性。6例免疫治疗有效好转,1例对症治疗后好转,其中2例患者病情严重并于治疗后半年死亡,余5例均明显好转。结论多种抗神经元抗体阳性的自身免疫性脑炎并不多见,临床表现更复杂多样,极易引起误诊或漏诊。潜在肿瘤风险更大,合并的肿瘤类型可能更广泛,加重病情、增加复发率及病死率,需引起高度重视,全面的实验室检查及定期复查是必要的。     

Ethanol inhibition of NMDA mediated depolarizations is increased in the presence of Mg

The inhibitory potency of ethanol upon excitatory amino acid induced depolarizations of rat hippocampal CA1 pyramidal cells was assessed in the presence and absence of magnesium (Mg²⁺) using the grease-gap technique. Ethanol shifted theN-methyl-d-aspartate (NMDA) dose-response curves to the right in a non-parallel manner. In the presence of Mg²⁺, ethanol appeared to be a more effective NMDA antagonist (IC₅₀ 47 mM) than in the absence of Mg²⁺ (IC₅₀ 107 mM). The IC₅₀ for ethanol upon non-NMDA mediated CA1 pyramidal cell depolarizations was in excess of 170 mM. These results strongly suggest a preferential inhibitory action of ethanol against NMDA, rather than non-NMDA, mediated responses. Experiments in which ethanol and Mg²⁺ were covaried indicated that these substances act by two distinct mechanisms to antagonize the action of NMDA. These effects of ethanol, at concentrations which elicit intoxication(< 50mM) but not anesthesia, suggest that the NMDA receptor complex may play an important role in the acute effects of ethanol.     

对Lancet Neurol发表的自身免疫性脑炎诊断路径的思考

正临床发生的脑实质炎症反应致脑炎是神经科常见疾病之一,其致病因素可以分为感染性因素和非感染性因素两大类[1],在非感染性因素中,自身免疫性脑炎占据重要位置。随着抗细胞内抗原抗体和抗细胞表面抗原抗体的发现,临床明确诊断的自身免疫性脑炎病例数逐渐增加,目前,临床医师对此类疾病的诊断主要依靠自身抗体检测和试验性免疫调节治疗[2],故在很大程度上限制了早期治疗方案的选择。由于早期免疫调节治疗可以显著改     

抗GABA_B受体脑炎5例报道及文献复习

目的探讨抗γ-氨基丁酸受体(GABA_BR)脑炎的临床特点及诊治。方法对5例抗GABA_BR脑炎患者临床表现、辅助检查等进行回顾性分析及文献回顾。结果 5例抗GABA_B抗体阳性患者均亚急性起病,表现为难治性癫痫,其中1例以性格改变、2例以抽搐、2例以记忆减退为首发症状。3例患者头部MRI显示边缘系统异常高信号,3例脑电图显示异常,2例脑脊液检查合并其它自身免疫抗体,2例肺部CT或PET-CT扫描提示肺部占位。经给予丙球或激素治疗明显好转。结论 (1)抗GABA_B受体脑炎首发症状多样,主要表现为难治性癫痫。(2)对于怀疑边缘性脑炎(LE)患者应筛查抗GABA_B受体抗体。(3)对抗GABA_B受体抗体阳性的患者应该积极进行肿瘤的筛查。     

Ethanol-induced state-dependent learning is mediated by 5-hydroxytryptamine3 receptors but not byN-methyl-d-aspartate receptor complex

Involvement ofN-methyl-d-aspartate (NMDA) receptor complex and 5-hydroxytryptamine₃ (5-HT₃) receptors in state-dependent learning (SDL) induced by ethanol (EtOH) was investigated in the step-through passive avoidance task in rats. Pre-training injections of EtOH or MK-801 reduced step-through latency in the test session conducted 24 h after the training session. Pre-test as well as pre-training injections of EtOH failed to reduce the latency, while pre-training and pre-test injections of MK-801 reduced the latency. These results show that EtOH but not MK-801 produces SDL. SDL induced by EtOH was blocked by ICS205-930 injected before either the training or test session. However, ICS205-930 failed to block SDL induced by diazepam and muscimol. These results suggest that NMDA receptor complex may not be involved in SDL, and that 5-HT₃ receptors may contribute to SDL induced by EtOH but not by diazepam and muscimol.     

Chronic neonatal MK-801 treatment results in an impairment of spatial learning in the adult rat

Chronic neonatal treatment with the non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist MK-801 from postnatal day 8 through 19 has been shown to affect hippocampal NMDA receptor function of adult rats. Since many studies have shown that NMDA receptors play a crucial role in learning and memory, and since one of the hippocampal functions is spatial learning, we have examined whether this changed response of hippocampal neurons is associated with changes in its normal function. We therefore tested spatial learning and memory using a water maze in adult rats neonatally treated with MK-801. MK-801-treated rats were able to learn the spatial task as well as control rats but at a significantly slower rate. Performance in a visual cue task was not affected by the neonatal treatment, suggesting that the slower spatial learning is not caused by locomotor or sensory deficits. These results suggest that chronic NMDA receptor blockade during the neonatal period leads to long-lasting disturbances of hippocampal function.     

Lesions in the bed nucleus of the stria terminalis, but not in the lateral septum, inhibit short-photoperiod-induced testicular regression in Syrian hamsters

The transfer of adult male hamsters from long days (LD) to short days (SD) (i.e. < 12 h of light per day) typically results in marked testicular regression and a decline in plasma testosterone concentrations. To help disclose key brain regions responsible for mediating this photoperiodic response male hamsters received either chemical (i.e. N-methyl-d-aspartate; NMDA) or radiofrequency current lesions in the bed nucleus of the stria terminalis (BNST), and were then exposed to SD for 15 or 12 weeks, respectively. Although body weights were similar between sham-lesioned controls and the NMDA-lesioned hamsters, the latter showed a significant attenuation of testicular regression; additionally, their plasma testosterone concentrations remained at typical LD levels. When radiofrequency current-lesioned hamsters were transferred from LD to SD they also failed to show significant signs of testicular regression, nor a decline in plasma testosterone concentrations, nor a complete arrest of spermatogenesis. In contrast, sham-lesioned controls or hamsters that were lesioned dorsally to the BNST at a site primarily involving the lateral septum all showed the expected degree of testicular regression, a decline in plasma testosterone concentrations, and complete arrest of spermatogenesis; body weights were similar in all of the experimental group. Taken together, these findings suggest that the BNST, a brain area traditionally not associated with reproductive function, may play an important role in mediating photoperiodic information to the neural circuits that control the reproductive axis.     

Evidence for an excitatory amino acid pathway in the brainstem and for its involvement in cardiovascular control

The source and possible role of excitatory amino acid projections to areas of the ventrolateral medulla (VLM) involved in cardiovascular control were studied. Following the injection of [3H]D-aspartate ([3H]D-Asp), a selective tracer for excitatory amino acid pathways, into vasopressor or vasodepressor areas of the VLM in rats, more than 90% of retrogradely labelled neurones were found in the nucleus of the solitary tract (NTS). Very few of the [3H]D-Asp-labelled cells were immunoreactive for tyrosine hydroxylase, none for phenylethanolamine-N-methyltransferase or gamma-aminobutyric acid. The density of labelled cells in the NTS was similar to that obtained with the non-selective tracers wheat germ agglutinin-horseradish peroxidase (WGA-HRP) and WGA-colloidal gold, but these tracers also labelled other cell groups in the medulla. Furthermore, the decrease in blood pressure, caused by pharmacological activation of neurones in the NTS of rats, or by electrical stimulation of the aortic depressor nerve in rabbits could be blocked by the selective N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate injected into the caudal vasodepressor area of the VLM. This area corresponds to the termination of [3H]D-Asp transporting NTS neurones. These results provide evidence that a population of NTS neurones projecting to the VLM use excitatory amino acids as transmitters. Among other possible functions, this pathway may mediate tonic and reflex control of blood pressure via NMDA receptors in the VLM.     

NMDA antagonists attenuate hypertension induced by carotid clamping in the rostral ventrolateral medulla of rats

The purpose of these experiments were to study the interactions of N-methyl-D-aspartate (NMDA) with baroreceptor reflexes induced by transient carotid clamping. Adult male Sprague-Dawley rats were anesthetized with urethane. Bilateral common carotid artery occlusion resulted in a reversible and reproducible hypertension in the vagotomized animals. This hypertensive reaction was blocked by intraventricular injection of NMDA antagonists, such as 2-amino-7-phosphono-heptaneoate (AP-7) and phencyclidine (PCP). We also found that blood pressure-sensitive neurons of the rostral ventrolateral medulla (RVLM) could be classified into two groups, on the basis of their responses to norepinephrine given intravenously. Using pressure microejection and single unit recording, we observed that clamping of the common carotids resulted in excitation of type I neurons. This evoked excitation, similar to that induced by NMDA, was blocked by locally applied AP-7. However, the carotid occlusion-induced responses of type II neurons were not blocked by AP-7. In conclusion, the present data suggest that NMDA receptors are involved in hypertensive responses during carotid occlusion, perhaps involving a site in the rostral ventrolateral medulla.     

Reduced density of NMDA receptors and increased sensitivity to dizocilpine-induced learning impairment in aged rats

About 20 min prior to training in a shock-motivated 14-unit T-maze, young (3-4 months) and aged (24-25 months) male Fischer-344 rats were given s.c. injections of either saline or dizocilpine (MK-801, 0.02 or 0.04 mg/kg), a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor. The aged rats showed a dose-dependent impairment in maze performance. Deficiencies were manifested as increases in errors, in runtime from start to goal, and in the number and duration of shocks received. In contrast, young rats exhibited no detrimental effects of dizocilpine on maze performance. Analysis of [3H]glutamate binding in these rats revealed a marked age-related decline in NMDA receptor binding in hippocampus. A significant correlation was observed between errors in the maze and hippocampal [3H]-glutamate binding, but the correlation was positive, i.e., rats that made the most errors had the highest level of NMDA receptor binding. Thus, compared to young rats, aged rats were more sensitive to the behavioral effects of NMDA receptor antagonism and they showed a hippocampal loss of [3H]glutamate in binding, which may be related to the increased sensitivity to dizocilpine. The positive correlation between poor maze performance and NMDA receptor binding suggests that the behaviors assessed involve complex interactions between NMDA receptors and other neuronal systems in the hippocampus.     

Epileptiform bursts elicited in CA3 hippocampal neurons by a variety of convulsants are not blocked by N-methyl-d-aspartate antagonists

Intracellular and extracellular recordings from CA₃ hippocampal neurons in vitro were used to study the ability of several NMDA (N-methyl-d-aspartate) receptor antagonists to suppress epileptiform bursts induced by NMDA and convulsants not thought to act at NMDA receptors. The antagonists, APV (d-2-amino-5-phosphonovalerate), AP-7 (d,l-2-amino-7-phosphonoheptanoate) and CPP (d,l-3-[(±)-2-car☐ypiperazin-4-yl-]-propyl-1-phosphonic acid), blocked the spontaneous and evoked bursts induced by NMDA. CPP, but not APV or AP-7, prevented the development of bursts induced by Mg-free medium. The NMDA antagonists failed to block bursting induced by kainate, 7 mM K⁺, mast cell degranulating peptide, anoxia or spontaneous bursting. In some cases the NMDA antagonists induced spontaneous bursts or enhanced burst frequency, a proconvulsant effect. It is concluded that activation of NMDA receptors is sufficient but not necessary for burst generation in the CA₃ region.