Pro-cognitive effects of dual tacrine derivatives acting as cholinesterase inhibitors and NMDA receptor antagonists.

Therapeutic options for Alzheimer's disease are limited. Dual compounds targeting two pathways concurrently may enable enhanced effect. The study focuses on tacrine derivatives inhibiting acetylcholinesterase (AChE) and simultaneously N-methyl-D-aspartate (NMDA) receptors. Compounds with balanced inhibitory potencies for the target proteins (K1578 and K1599) or increased potency for AChE (K1592 and K1594) were studied to identify the most promising pro-cognitive compound. Their effects were studied in cholinergic (scopolamine-induced) and glutamatergic (MK-801-induced) rat models of cognitive deficits in the Morris water maze. Moreover, the impacts on locomotion in the open field and AChE activity in relevant brain structures were investigated. The effect of the most promising compound on NMDA receptors was explored by in vitro electrophysiology. The cholinergic antagonist scopolamine induced a deficit in memory acquisition, however, it was unaffected by the compounds, and a deficit in reversal learning that was alleviated by K1578 and K1599. K1578 and K1599 significantly inhibited AChE in the striatum, potentially explaining the behavioral observations. The glutamatergic antagonist dizocilpine (MK-801) induced a deficit in memory acquisition, which was alleviated by K1599. K1599 also mitigated the MK-801-induced hyperlocomotion in the open field. In vitro patch-clamp corroborated the K1599-associated NMDA receptor inhibitory effect. K1599 emerged as the most promising compound, demonstrating pro-cognitive efficacy in both models, consistent with intended dual effect. We conclude that tacrine has the potential for development of derivatives with dual in vivo effects. Our findings contributed to the elucidation of the structural and functional properties of tacrine derivatives associated with optimal in vivo pro-cognitive efficacy.

Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn.

OBJECTIVE: To investigate whether the Chinese massage system, Tuina, exerts analgesic effects in a rat model of chronic constriction injury (CCI) by remodeling the synaptic structure in the spinal cord dorsal horn (SCDH). METHODS: Sixty-nine male Sprague-Dawley rats were randomly and evenly divided into the normal group, sham group, CCI group, CCI + Tuina group, CCI + MK-801 [an -methyl D-aspartate receptor subtype 2B (NR2B) antagonist] group, and CCI + MK-801 + Tuina group. The neuropathic pain model was established using CCI with right sciatic nerve ligation. Tuina was administered 4 d after CCI surgery, using pressing manipulation for 10 min, once daily. Motor function was observed with the inclined plate test, and pain behaviors were observed by the Von Frey test and acetone spray test. At 19 d after surgery, the L3-L5 spinal cord segments were removed. Glutamate, interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) levels were detected by enzyme-linked immunosorbent assay. The protein expression levels of NR2B and postsynaptic density protein-95 (PSD-95) were detected by Western blot, and the synaptic structure was observed by transmission electron microscopy (TEM). RESULTS: CCI reduced motor function and caused mechanical and cold allodynia in rats, increased glutamate concentration and TNF-α and IL-1ß levels, and increased expression of synapse-related proteins NR2B and PSD-95 in the SCDH. TEM revealed that the synaptic structure of SCDH neurons was altered. Most of these disease-induced changes were reversed by Tuina and intrathecal injection of MK-801 ( < 0.05 or < 0.01). For the majority of experiments, no significant differences were found between the CCI + MK-801 and CCI + MK-801 + Tuina groups. CONCLUSIONS: Chinese Tuina can alleviate pain by remodeling the synaptic structure, and NR2B and PSD-95 receptors in the SCDH may be among its targets.

Antisense oligodeoxynucleotides against dynamin-related protein 1 reduce remifentanil-induced hyperalgesia by modulating spinal N-methyl-D-aspartate receptor expression in rats.

Background: Spinal N-methyl-D-aspartate (NMDA) receptor activation is attributed to remifentanil-induced hyperalgesia (RIH). However, the specific mechanism and subsequent treatment is still unknown. Previous studies have shown that the dynamin-related protein 1 (DRP1)-mitochondria-reactive oxygen species (ROS) pathway plays an important role in neuropathic pain. This study examined whether antisense oligodeoxynucleotides against DRP1 (AS-DRP1) could reverse RIH. Methods: The authors first measured changes in paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL) at 24 hours before remifentanil infusion and 4, 8, 24, and 48 hours after infusion. The expression levels of DRP1 and NR2B were measured after behavioral testing using Western blotting. In addition, DRP1 expression was knocked down by intrathecal administration of AS-DRP1 to investigate the effects of DRP1 on RIH. The behavioral testing, the expression levels of spinal DRP1 and NR2B, and dorsal mitochondrial superoxide were measured. Changes in mitochondrial morphology were assessed using electron microscopy. Results: After remifentanil exposure, upregulation of spinal DRP1 and NR2B was observed along with a reduction in PWMT and PWTL. In addition, AS-DRP1 improved RIH-induced PWTL and PWMT (P < 0.001 and P < 0.001) and reduced remifentanil-mediated enhancement of spinal DRP1 and NR2B expression (P = 0.020 and P = 0.022). More importantly, AS-DRP1 reversed RIH-induced mitochondrial fission (P = 0.020) and mitochondrial superoxide upregulation (P = 0.031). Conclusions: These results indicate that AS-DRP1 could modulate NMDA receptor expression to prevent RIH through the DRP1-mitochondria-ROS pathway.

Etomidate-ketamine versus dexmedetomidine-ketamine for entropy-guided procedural sedation during endoscopic retrograde cholangiopancreatography procedures: A randomized single blind study.

BACKGROUND AND AIMS: The major challenge for the anesthetist in endoscopic retrograde cholangiopancreatography (ERCP) procedures is to provide moderate to deep levels of sedation in prone position with preservation of spontaneous respiratory efforts in shared airway scenario with an endoscopist. These patients have other comorbidities, making them vulnerable to complications during the routinely used sedation with propofol. We compared the entropy-guided efficacy of combination of etomidate-ketamine to dexmedetomidine-ketamine in patients undergoing ERCP. METHODS: This prospective single blind randomized entropy-guided trial was conducted on 60 patients with etomidate-ketamine in group I (n = 30) and dexmedetomidine-ketamine in group II (n = 30). The purpose was to compare etomidate-ketamine versus dexmedetomidine-ketamine for ERCP in terms of intraprocedural hemodynamics with desaturation, onset of sedation, recovery time and endoscopist's satisfaction. RESULTS: Hypotension was observed only in six (20%) patients of group II (p < 0.009). Two patients of group I and three in group II desaturated (Spo2 < 90) briefly during the procedure, but none of the patient required intubation (p > 0.05). The mean time in minutes of onset of sedation was 1.15 in group I and 5.6 in group II (p < 0.001). Endoscopists' satisfaction was better in group I (p ≤ 0.001) and length of recovery room stay was shorter in group I as compared to that in group II (p ≤ 0.007). CONCLUSION: We conclude that entropy-guided intravenous procedural sedation with etomidate-ketamine combination provides faster onset of sedation, stable periprocedural hemodynamics, rapid recovery and fair to excellent endoscopist satisfaction compared to dexmedetomidine-ketamine combination for ERCP.

Advances in relapse risk factors of anti-N-methyl-D-aspartate receptor encephalitis / 中华神经科杂志

Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune encephalitis mediated by anti-NMDAR antibody. Current studies have found that most patients with anti-NMDAR encephalitis have a good prognosis after immunotherapy and tumor therapy, but there are still 4.5%-36.4% patients with relapse. It is important to identify the risk factors for the prevention of relapse. This article aims to review the relapse risk factors of NMDAR encephalitis in order to provide help for the prevention of relapse.

Coexisting anti-N-methyl-D-aspartate receptor and anti-glutamic decarboxylase antibody- associated encephalitis after herpes simplex virus encephalitis: a case report / 中华神经科杂志

Herpes simplex virus encephalitis (HSE) is a common form of viral encephalitis, often with a single-phase course. A case of HSE with abnormal mental behavior as the main manifestation, admitted in Peking University Shenzhen Hospital in Octorber 2020, which improved after sufficient antiviral treatment was reported. After 2 months, abnormal mental behavior with memory deterioration recurred. It was considered as anti-N-methyl-D-aspartate receptor antibody combined with anti-glutamic decarboxylase antibody double-positive encephalitis, and improved after rituximab treatment. At present, there is no clinical report of such double antibody positive autoimmune encephalitis secondary to HSE. The purpose of this case report is to raise clinician awareness of post-HSE autoimmune encephalitis.

Role of NMDA receptors in sevoflurane anesthesia-caused necroptosis in hippocampal neurons of aged mice / 中华麻醉学杂志

Objective:To evaluate the role of N-methyl-D-aspartate receptors (NMDA receptors) in sevoflurane anesthesia-caused necroptosis in hippocampal neurons of aged mice.Methods:Ninety clean-grade healthy male C57BL/6 mice, aged 18 months, weighing 27-30 g, were divided into 3 groups ( n=30 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S) and sevoflurane anesthesia plus NMDA receptor antagonist memantine hydrochloride group (group S+ M). Mice inhaled 3% sevoflurane for 2 h for 3 consecutive days in S group and S+ M group, and memantine hydrochloride 20 mg/kg was intraperitoneally injected at 1 h before each inhalation of sevoflurane in S+ M group.Mice only inhaled pure oxygen for 2 h in group C. Ten mice of each group were selected on 1 day before anesthesia and 3 and 7 days after anesthesia to perform Morris water maze test.The mice were sacrificed immediately after Morris water maze test, and hippocampus was removed for microscopic examination of pathological changes (with a light microscope) and for determination of the necroptosis rate of neurons and cytoplasmic free calcium concentration([Ca 2+ ] i)(by flow cytometry), and expression of NMDA receptor subtypes GluN2A, GluN2B and receptor-interacting protein kinase 1 (RIP1) (by Western blot). Results:Compared with group C, the escape latency was significantly prolonged, and the frequency of crossing the original platform was decreased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were increased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was up-regulated( P<0.05), and the pathologic changes were accentuated in S group and S+ M group.Compared with group S, the escape latency was significantly shortened, and the frequency of crossing the original platform was increased, and the [Ca 2+ ] i and neuronal necroptosis rate in the hippocampus were decreased at each time point after anesthesia, and the expression of GluN2A, GluN2B and RIP1 was down-regulated ( P<0.05), and the pathologic changes were attenuated in group S+ M. Conclusions:NMDA receptors are involved in the process of cognitive dysfunction induced by sevoflurane anesthesia in aged mice, and the mechanism may be related to the promotion of necrptosis in hippocampal neurons.

Tongluo Huatan capsule improves cognitive function by regulating the endocytosis of N-methyl-D-aspartic acid receptors mediated by clathrin in a rat model of vascular dementia.

OBJECTIVE: To explore the neuroprotective mechanisms of Tongluo Huatan capsule (THC) in a rat model of vascular dementia (VD). METHODS: A rat model of VD was established by repeated clamping of bilateral common carotid arteries with the intraperitoneal injection of sodium nitroprusside solution. VD rats were administered THC, memantine hydrochloride, or distilled water daily for 14 d after operation. Learning and memory abilities were assessed using the step-down passive avoidance test, novel object recognition (NOR) test, and Morris water maze (MWM) test. Pathological changes in the hippocampus were observed through hematoxylin and eosin and Nissl staining. The expression levels of clathrin, RAB5B, and N-methyl-D-aspartic acid receptor 1 (NMDAR1) were measured by immunohistochemistry staining, real-time quantitative polymerase chain reaction and Western blot. RESULTS: Rats in VD group showed impaired learning and memory abilities (step-down passive avoidance, NOR, and MWM) and abnormalities in neuronal morphology (light microscopy) in the hippocampus. The mRNA or protein expression levels of clathrin and RAB5B were decreased, and NMDAR1 was increased in hippocampal tissues (P < 0.05). Administration of THC promoted the learning and memory abilities and the morphological structure of hippocampal neurons in VD rats. Besides, THC enhanced mRNA or protein expression levels of clathrin and RAB5B, and decreased NMDAR1 (P < 0.05). CONCLUSION: THC may improve cognitive functions by regulating the endocytosis of NMDA receptors mediated by clathrin.

Clinical characteristics of movement disorders in patients with anti-N-methyl-D-aspartate acid receptor encephalitis / 中华神经科杂志

Objective:To explore the clinical characteristics, therapeutic effect and prognosis of movement disorders in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.Methods:The prospectively collected data of hospitalized 163 patients with anti-NMDAR encephalitis admitted to Xuanwu Hospital, Capital Medical University from June 2012 to October 2019 were analyzed. According to the presence of movement disorders, the patients were divided into movement disorders group (75 cases, 46.0%) and non-movement disorders group (88 cases, 54.0%). Patients were followed up for six months and 12 months after immunotherapy. The clinical manifestations, auxiliary examinations, treatment and prognosis of the two groups were compared.Results:Among 163 patients with anti-NMDAR encephalitis, 91 patients (55.8%) were male and 72 patients (44.2%) were female, with an age of 26(19, 34) years. In the 75 patients of the movement disorders group, 50 patients (66.7%) presented with orofacial dyskinesia, 45 patients (60%) with limb stereotypies, 28 patients (37.3%) with choreoathetosis, nine patients (12.0%) with ballism, seven patients (9.3%) with bradykinesia, five patients (6.7%) with tremor, and 13 patients (17.3%) with status dystonicus. Compared with the non-movement disorders group, the movement disorders group had a higher proportion of ovarian teratoma (14.7% vs 3.4%), modified Rankin Scale score of 3-5 before immunotherapy (76.0% vs 33.0%), abnormal electroencephalogram (89.3% vs 77.3%), increased lumbar puncture pressure (53.3% vs 34.1%), cerebrospinal fluid (CSF) pleocytosis (73.3% vs 51.1%), strong positive NMDAR antibody of CSF (44.0% vs 25.0%), admitting to intensive care unit (60.0% vs 9.1%), treated with intravenous immunoglobulin (80.0% vs 40.9%), plasma exchange (36.0% vs 3.4%), and immunosuppressive therapy (37.2% vs 17.0%); had shorter days from the onset to the beginning of immunotherapy [20(10, 33) d vs 35(15, 77) d]; had longer days from the beginning of immunotherapy to the improvement [34(20, 60) d vs 20(15, 35) d]; and there were significant differences of above items between the two groups ( P<0.05). There was no significant difference in the prognosis and relaps between the two groups at six and 12 months after immunotherapy. Conclusions:Nearly a half of patients with anti-NMDAR encephalitis had movement disorders with multiple phenotypes. The severity of movement disorders was related to the severity of the disease. After active immunotherapy and symptomatic treatment, movement disorders improved with the improvement of primary disease in majority of patients.

Analysis of clinical characteristics of patients with anti-myelin oligodendrocyte glycoprotein and anti-N-methyl-D-aspartate receptor antibody positive / 中华神经科杂志

Objective:To analyze the clinical characteristics of patients with double-positive anti-myelin oligodendrocyte glycoprotein (MOG) antibody and anti-N-methyl-D-aspartate receptor (NMDAR) antibody, so as to raise awareness of such diseases and improve the prognosis.Methods:Eighteen patients (double positive group) with positive serum anti-MOG antibody and cerebrospinal fluid anti-NMDAR antibody in Huashan Hospital, Fudan University from March 2017 to March 2020 were retrospectively analyzed. Using the SPSS software for simple random sampling, anti-MOG group(20 cases) and anti-NMDAR group (20 cases) were randomly selected at the same time for comparison. The anti-MOG group referred to the patients only with positive serum anti-MOG antibody. While the anti-NMDAR group referred to the patients whose cerebrospinal fluid anti-NMDAR antibody was positive. The clinical characteristics, laboratory examination results, radiological characteristics and prognosis of the three groups were collected and analyzed.Results:There was no statistically significant difference in demographic data among the three groups ( P>0.05). The symptoms of patients in the double-positive group were divided into two categories by cluster analysis, which corresponded to the symptom groups obtained by cluster analysis of the anti-MOG group and the anti-NMDAR group, and the same result was verified by correspondence analysis. Compared with the anti-MOG group, the incidence of epilepsy (10/18 vs 3/20, P=0.016), psychosis and behavior change (8/18 vs 0/20, P=0.001), visual disturbances (8/18 vs 17/20, P=0.016), dysarthria/dysphagia (8/18 vs 1/20, P=0.007) was significantly different in the double-positive group ( P<0.017). Compared with the anti-NMDAR group, the incidence of ataxia (8/18 vs 19/20, P=0.001), psychosis and behavior change (12/18 vs 1/20, P<0.001) was significantly different in the double-positive group. There was no statistically significant difference in the combination rate of thyroid peroxidase antibody, thyroglobulin antibody and antinuclear antibody between two groups, and the cerebrospinal fluid pressure, white blood cell count, protein, glucose, chloride and positive rate of oligoclonal band were also not statistically different between two groups ( P>0.017; P<0.017 indicates statistically significant difference by Bonferroni corrected multiple comparisons). Compared with the anti-NMDAR group, whether the brain magnetic resonance imaging had lesions was different in double positive group (18/18 vs 8/20, P<0.001). The initial modified Rankin Scale (mRS) scores before treatment were different among the double positive group, anti-MOG group and anti-NMDAR group (3.72±0.96, 2.75±0.97, 3.95±0.76, respectively, F=10.004, P<0.001), but there was no statistically significant difference in the scores after six-month treatment (1.22±1.44, 0.40±0.75, 1.20±1.24, respectively, F=3.153, P=0.051), and the recurrence rate of the disease was different among the three groups (8/18, 14/20, 5/20, respectively, χ2=10.004, P=0.017). Conclusions:Anti-MOG antibodies and anti-NMDAR antibodies could exist at the same time, showing clinical phenotype overlap, which was a new syndrome called the overlapping syndrome of myelin oligodendrocyte glycoprotein antibody-associated disease and NMDAR encephalitis, MNOS. The condition of MNOS patients was more severe than that of patients with MOG antibody-associated disease (MOGAD), but patients with MNOS, MOGAD, and anti-NMDAR encephalitis all responded well to immunosuppressive therapy. It was suggested that early second-line immunotherapy should be given to reduce the recurrence rate in patients with MNOS and MOGAD.

Role of spinal P2Y1R in development of remifentanil-induced hyperalgesia in rats with incisional pain: relationship with function of NR1 and NR2B in spinal cord / 中华麻醉学杂志

Objective:To evaluate the role of spinal P2Y1R in the development of remifentanil-induced hyperalgesia in rats with incisional pain (IP) and the relationship with the function of NR1 and NR2B in spinal cord.Methods:Forty-eight healthy adult male Sprague-Dawley rats, aged 10-12 weeks, weighing 250-280 g, in which intrathecal catheters were successfully placed, were divided into 6 groups ( n=8 each) using a random number table method: control group (group C), P2Y1R antagonist MRS2179 group (group M), remifentanil group (group R), remifentanil plus MRS2179 group (group R+ M), IP plus remifentanil group (group I+ R) and IP plus remifentanil plus MRS2179 group (group I+ R+ M). In group C, normal saline 10 μl was intrathecally injected, and 10 min later normal saline was infused for 60 min via the tail vein at a rate of 0.1 ml·kg -1·min -1.In group M, MRS2179 0.6 nmol/kg was intrathecally injected, and 10 min later normal saline was infused for 60 min via the tail vein at a rate of 0.1 ml·kg -1·min -1.In group R, normal saline 10 μl was intrathecally injected, and 10 min later remifentanil was infused for 60 min via the tail vein at a rate of 1 μg·kg -1·min -1.In group R+ M, MRS2179 0.6 nmol/kg was intrathecally injected, and 10 min later remifentanil was infused for 60 min at a rate of 1 μg·kg -1·min -1 via the tail vein.In group I+ R, normal saline 10 μl was intrathecally injected, 10 min later remifentanil was infused for 60 min via the tail vein at a rate of 1 μg·kg -1·min -1, and IP was established at 10 min after onset of remifentanil infusion.In group I+ R+ M, MRS2179 0.6 nmol/kg was intrathecally injected, 10 min later remifentanil was infused via the tail vein for 60 min at a rate of 1 μg·kg -1·min -1, and IP was established at 10 min after onset of remifentanil infusion.The mechanical paw withdrawal threshold (MWT), thermal paw withdrawal latency (TWL), and the number of paw lifts on the cold plate were measured at 24 h before infusion of remifentanil or normal saline and at 2, 6, 24, and 48 h after the end of infusion.The animals were sacrificed after the last measurement of the pain threshold, L 4-6 segments of the spinal cord were removed for determination of the expression of P2Y1R, phosphorylated NR1 (p-NR1), NR1, phosphorylated NR2B (p-NR2B) and NR2B (by Western blot), for calculation of the ratios of p-NR1/NR1 and p-NR2B/NR2B, and for detection of expression of P2Y1R mRNA, NR1 mRNA and NR2B mRNA (by real-time polymerase chain reaction). Results:Compared with group C, MWT was significantly decreased, TWL was shortened, the number of paw lifts on the cold plate was increased, the expression of P2Y1R protein and mRNA, NR1 protein and mRNA, p-NR1, NR2B protein and mRNA and p-NR2B was up-regulated, and p-NR1/NR1 ratio and p-NR2B/NR2B ratio were increased in group R ( P<0.01). Compared with group R, MWT was significantly increased, TWL was prolonged, the number of paw lifts on the cold plate was decreased, the expression of P2Y1R, p-NR1, NR1 protein and mRNA, p-NR2B, NR2B protein and mRNA was down-regulated, and p-NR1/NR1 ratio and p-NR2B/NR2B ratio were decreased in group R+ M ( P<0.05 or 0.01). Compared with group I+ R, MWT was significantly increased, TWL was prolonged, the number of paw lifts on the cold plate was decreased, the expression of P2Y1R, p-NR1, NR1 protein and mRNA, p-NR2B, NR2B protein and mRNA was down-regulated, and p-NR1/NR1 ratio and p-NR2B/NR2B ratio were decreased in group I+ R+ M ( P<0.01). Conclusion:Spinal P2Y1R can enhance the function of NR1 and NR2B, which may be involved in the development of remifentanil-induced hyperalgesia in rats with IP.

[Clinical approach and prognosis of continuous neurological care after intensive care for the patients with severe and refractory anti-N-methyl-D-aspartate receptor encephalitis].

Objective: To study the clinical features, continuous care and prognosis of the patients with severe and refractory anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis after intensive care unit (ICU). Methods: Clinical data of patients with severe and refractory anti-NMDAR encephalitis, who were transferred from ICU to general ward of neurology between December 2015 and October 2019, were retrospectively reviewed and analyzed in the study. Results: Twenty patients (11 females and 9 males) were enrolled in the study. The median course of disease when patients were transferred to general ward was 4.4 (2.0, 6.0) months. Six cases were alert, 6 cases were in a coma, 5 were in the early recovery phase and 3 were in the late recovery phase. Severe malnutrition, pneumonia, urinary tract infections, bedsores and leukocytopenia were common complications. Seven out of 18 patients were tested positive for cerebrospinal fluid anti-NMDAR antibodies with high titers (≥1∶100). During this continuous therapy stage,10 patients were treated with intravenous immunoglobulin (IVIg), 1 with methylprednisolone, 2 with rituximab, 1 with intrathecal methotrexate and 1 received intravenous cyclophosphamide. All Patients were prescribed a long-term immunotherapy (mycophenolate mofetil 1.5-3.0 g/d). Sixteen patients (80%) had good prognosis (modified Rankin Scale (mRS)≤2), and the mortality was 10%, with follow-up time of 17.0 (8.0, 27.0) months. Conclusions: Patients with anti-NMDAR encephalitis, who are transferred from ICU, have severely impaired neurologic function. These patients need long-term individualized immunotherapy and continuous neurological care. Good outcomes can be achieved in most patients.

[Cognitive function and cerebral blood perfusion changes in patients with anti-N-methyl-D-aspartate receptor encephalitis].

Objective: To investigated cognitive and cerebral blood flow changes in a cohort of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods: Fifteen patients with confirmed anti-NMDAR encephalitis from the First Affiliated Hospital of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China between June 2015 and February 2019 were included in the study. Meanwhile, another 15 healthy subjects were selected as controls. All participants underwent neuropsychological tests for assessment of the clinical symptoms and arterial spin labeling (ASL) of magnetic resonance perfusion imaging scan were employed to evaluate cerebral perfusion. Then the relationship between changed cerebral blood perfusion and cognitive function was evaluated. Results: Patients with anti-NMDAR encephalitis showed significantly reduced overall cognitive function (Montreal cognitive assessment (MoCA)) than healthy controls (26.5±2.5 vs 28.6±1.9, P=0.015), they also exhibited poorer performance in immediate memory, recognition, attention, language and executive function than healthy controls (P<0.05). However, no significant differences in clinical symptoms, viability, mental state and mood were observed between the two groups (P>0.05). Patients with anti-NMDAR encephalitis showed significantly reduced total brain cerebral blood flow (CBF) compared with the healthy controls (0.949±0.028 vs 0.953±0.025, P=0.001). Compared with the healthy controls, the patients had decreased CBF in triangular and opercular parts of bilateral inferior frontal gyrus and left central frontal gyrus, however, they showed increased CBF in the left inferior temporal gyrus and left fusiform gyrus (all P<0.05). In NMDAR group, the CBF in left central anterior gyrus was negatively correlated with Stroop's Color Word-word (r=-0.68, P=0.005). The CBF in left spindle gyrus was positively correlated with Stroop's Color Word-word (r=0.62, P=0.015) and completion time of color trail test-A (r=0.81, P<0.001), respectively, however, it was negatively correlated with Chinese Auditory Verbal Learning Test-immediate (r=-0.59, P=0.020) and Verbal Fluency Test-animals (r=-0.58, P=0.024), respectively. Conclusions: Patients with anti-NMDAR encephalitis have prevalent cognitive deficits such as memory, language, attention and executive dysfunction as well as changes in blood perfusion, which may be related to cognitive deficits. Changes in cerebral blood perfusion can be used as indicators for early diagnosis, disease monitoring and prognosis evaluation of anti-NMDAR encephalitis. Improving the cerebral blood flow of patients may promote the recovery of cognition.

Optic Nerve Atrophy in N-methyl-D-aspartate (NMDA) Encephalitis.

N-methyl-D-aspartate receptor (NMDA) encephalitis is a recently described autoimmune disease that typically presents with prodromal symptoms including upper respiratory tract infection, headache, fever, nausea, vomiting and diarrhea. Psychiatric symptoms follow within weeks, including anxiety, insomnia, mania, paranoia and grandiose delusions. The diagnosis is confirmed by the detection of NMDA antibodies in the serum or cerebrospinal fluid (CSF).1 Tumours, especially teratomas, are frequently associated with NMDA encephalitis; however, only 5% of male patients older than 18 years have been found to have an underlying tumour. Optic neuropathy associated with NMDA encephalitis is being increasingly recognised in the literature2-6 and was reviewed most recently by Mugavin et al.2 in 2017. In this report, we present a case of bilateral optic neuropathy in a young man diagnosed with NMDA receptor encephalitis.

[Clinical analysis of 71 cases of anti-N-methyl-D-aspartate receptor encephalitis in children].

Objective: To investigate the clinical features, treatment strategies and long term outcomes of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods: The data of clinical features, auxiliary examinations, treatments and prognosis in children with anti-NMDAR encephalitis in Xiangya Hospital of Central South University from March 2014 to October 2017 were collected and retrospectively analyzed. A total of 71 patients were enrolled, including 33 males and 38 females. The youngest age of onset was 4 months old, and the age of onset was (9±4) years. The first-line immunotherapy treatment for anti-NMDAR encephalitis was short course corticosteroid (high-dose impulse therapy and oral maintenance therapy for 1 month in acute period) and (or) immunoglobulin. The clinical evaluation was performed 2 weeks after first-line immunotherapy treatment. The second-line immunotherapy treatment, including rituximab and (or) cyclophosphamide, would be started if the symptoms did not improve significantly and the modified Rankin scale (mRS) score ≥3. All patients were followed up and evaluated for prognosis. T-test, Mann-Whitney U, Chi square test and Fisher's exact probability method were used for comparison between good outcome group and poor outcome group, first-line immunotherapy group and first-line immunotherapy combined with second-line immunotherapy group. Results: The more common clinical manifestations were psychiatric symptoms (n=61, 86%), dyskinesia (n=55, 77%) and convulsions (n=51, 72%). Two cases (3%) had tumors. Electroencephalogram (EEG), cerebro-spinal fluid (CSF) and brain magnetic resonance imaging (MRI) studies were abnormal in 83% (59/71), 39% (27/69) and 38% (27/71) patients, respectively. For the treatment regimens, all the 71 patients underwent first-line immunotherapy, resulting in improvement within 14 days in 40 cases (56%), and 1 case (1%) died. The rest 30 cases (42%) received second-line immunotherapy. The patients were followed up for 5.0-41.8 months, with a median of 19.3 months. At the last follow-up, 49 cases (69%) recovered completely, 15 cases (21%) had mild disability, 6 cases (8%) had severe disability, 1 case (1%) died and 3 cases (4%) had relapse. There were significant differences between the groups with good prognosis and poor prognosis on admission to pediatric intensive care unit (PICU) and consciousness disorder (10/64 vs. 5/7, 39/64 vs. 7/7, P=0.047, 0.004). There were significant differences between first-line immunotherapy group and the first-line combined second-line immunotherapy group on admission to PICU, consciousness disorder, sleep disorder and first mRS score (12% (5/41) vs. 33% (10/30), 44% (18/41) vs. 93% (28/30), 56% (23/41) vs. 90% (27/30), 3 (1-5) vs. 4 (3-5), respectively; χ(2)=4.645, 18.555, 9.560, Z=5.184, P=0.031, <0.01, 0.002, <0.01, respectively). Conclusions: Anti-NMDAR encephalitis can occur in all ages of children. The most common clinical manifestations are psychotic symptoms, dyskinesia and convulsions. Paraneoplastic cases are less common in children. Immunotherapy is effective. The second-line immunotherapy should be given after the failure of first-line therapy (mRS score≥3).

Antibody-related central nervous system autoimmune diseases: exploration and challenge / 中华神经科杂志

Antibody-related central nervous system (CNS) autoimmune diseases are a frontier of neuroimmunology.CNS viral infections including herpes simplex encephalitis and Japanese encephalitis can induce anti-N-methyl-D-aspartic acid receptor encephalitis with a double-peak presentation.Pathogenic antibody is the specific diagnostic biomarker which renders the establishment of new autoimmune entities.However,the pathogenicity and clinical relevance of some new antibodies need further evaluation.The challenge from cases with overlapping antibodies or antibody-negative limbic encephalitis can be solved with the reference to the diagnostic criteria and recommendation.

Research progress of anti-N-methyl-D-aspartate receptor antibody / 中华检验医学杂志

Anti-N-methyl-D-aspartate receptor (NMDAR) antibody is an autoimmune encephalitis antibody associated with Anti-NMDAR encephalitis.Since the discovery of the antibody in 2007,the basic research and clinical application of the antibody in the field of neuroimmunology have gradually increased.This article reviews the progress of anti-NMDAR antibody overview,the relationship between anti-NMDAR antibody and encephalitis,and the laboratory detection of anti-NMDAR antibody,so as to provide a reference for clinical diagnosis and treatment.

Progress in research on the role of cannabinoid receptor 1 signaling pathway in epilepsy / 中华神经科杂志

Epilepsy,a group of chronic neurological disorders characterized by spontaneous and recurrent seizures and learning and memory impairments,results in transient brain dysfunction due to sudden abnormal discharge of brain neurons.The pathogenesis of epilepsy is very complicated and has not yet been fully elucidated.The imbalance between excitatory glutamate and inhibitory gamma-aminobutyric acid (GABA) neurotransmitters in the central nervous system and changes in ionic functions of N-methyl-D-aspartate receptors directly induce epileptic seizures.The endocannabinoid system plays an important role in retrograde synaptic transmission and exerts the anti-epileptic effect in cannabinoid receptor 1 (CBR1) dependent manner by regulating the synaptic transmission of glutamatergic and GABAergic neurons and homeostatsis of ionic channel function.Elucidating the specific mechanism of action of CBR1 signaling pathway in epilepsy,can provide an effective theoretical basis and novel drug's target for clinical treatment of epilepsy.

Role of NR2B in sevoflurane anesthesia-induced cognitive dysfunction in aged rats / 中华麻醉学杂志

Objective@#To evaluate the role of 2B-containing NMDA receptors (NR2B) in sevoflurane anesthesia-induced cognitive dysfunction in aged rats.@*Methods@#Thirty-two healthy male Sprague-Dawley rats, aged 18 months, weighing 570-630 g, were divided into 4 groups (n=8 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S), sevoflurane anesthesia plus NR2B specific inhibitor Ro 25-6981 group (group S+ RO) and Ro 25-6981 group (group RO). S and S+ RO groups inhaled 3% sevoflurane for 4 h. Ro 25-6981 1 mg/kg was intraperitoneally injected at 15 min before inhaling sevoflurane in group S+ RO.Morris water maze test was performed at 2 days after the end of anesthesia to assess cognitive function.The rats were then sacrificed, and hippocampal tissues were obtained for determination of the expression and phosphorylation of ERK1/2 by Western blot.@*Results@#Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was reduced, the time of staying at the original platform quadrant was shortened, and the phosphorylation of ERK1/2 was decreased in group S (P<0.05), and no significant change was found in the escape latency in S+ RO and RO groups (P>0.05). Compared with group S, the escape latency was significantly shortened, the frequency of crossing the original platform was increased, the time of staying at the original platform quadrant was prolonged, and the phosphorylation of ERK1/2 was increased in group S+ RO(P<0.05). There was no significant difference in ERK1/2 expression among the four groups (P>0.05).@*Conclusion@#The mechanism by which sevoflurane anesthesia induces cognitive dysfunction is related to up-regulating the expression of NR2B and inhibiting the activity of ERK1/2 in aged rats.

Clinical analysis of 71 cases of anti-N-methyl-D-aspartate receptor encephalitis in children / 中华儿科杂志

Objective@#To investigate the clinical features, treatment strategies and long term outcomes of children with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis.@*Methods@#The data of clinical features, auxiliary examinations, treatments and prognosis in children with anti-NMDAR encephalitis in Xiangya Hospital of Central South University from March 2014 to October 2017 were collected and retrospectively analyzed. A total of 71 patients were enrolled, including 33 males and 38 females. The youngest age of onset was 4 months old, and the age of onset was (9±4) years. The first-line immunotherapy treatment for anti-NMDAR encephalitis was short course corticosteroid (high-dose impulse therapy and oral maintenance therapy for 1 month in acute period) and (or) immunoglobulin. The clinical evaluation was performed 2 weeks after first-line immunotherapy treatment. The second-line immunotherapy treatment, including rituximab and (or) cyclophosphamide, would be started if the symptoms did not improve significantly and the modified Rankin scale (mRS) score ≥3. All patients were followed up and evaluated for prognosis. T-test, Mann-Whitney U, Chi square test and Fisher′s exact probability method were used for comparison between good outcome group and poor outcome group, first-line immunotherapy group and first-line immunotherapy combined with second-line immunotherapy group.@*Results@#The more common clinical manifestations were psychiatric symptoms (n=61, 86%), dyskinesia (n=55, 77%) and convulsions (n=51, 72%). Two cases (3%) had tumors. Electroencephalogram (EEG), cerebro-spinal fluid (CSF) and brain magnetic resonance imaging (MRI) studies were abnormal in 83% (59/71), 39% (27/69) and 38% (27/71) patients, respectively. For the treatment regimens, all the 71 patients underwent first-line immunotherapy, resulting in improvement within 14 days in 40 cases (56%), and 1 case (1%) died. The rest 30 cases (42%) received second-line immunotherapy. The patients were followed up for 5.0-41.8 months, with a median of 19.3 months. At the last follow-up, 49 cases (69%) recovered completely, 15 cases (21%) had mild disability, 6 cases (8%) had severe disability, 1 case (1%) died and 3 cases (4%) had relapse. There were significant differences between the groups with good prognosis and poor prognosis on admission to pediatric intensive care unit (PICU) and consciousness disorder (10/64 vs. 5/7, 39/64 vs. 7/7, P=0.047, 0.004). There were significant differences between first-line immunotherapy group and the first-line combined second-line immunotherapy group on admission to PICU, consciousness disorder, sleep disorder and first mRS score (12% (5/41) vs. 33% (10/30), 44% (18/41) vs. 93% (28/30), 56% (23/41) vs. 90% (27/30), 3 (1-5) vs. 4 (3-5), respectively; χ2=4.645, 18.555, 9.560, Z=5.184, P=0.031, <0.01, 0.002, <0.01, respectively).@*Conclusions@#Anti-NMDAR encephalitis can occur in all ages of children. The most common clinical manifestations are psychotic symptoms, dyskinesia and convulsions. Paraneoplastic cases are less common in children. Immunotherapy is effective. The second-line immunotherapy should be given after the failure of first-line therapy (mRS score≥3).