In-silico Screening and Synthesis of Benzo[c]pyridazines Targeting N-methyl D-Aspartate Glutamate Receptor for the treatment of Seizures.

This study focuses on synthesizing novel benzopyridazine compounds with an evaluation of their anti-epileptic activity by in-silico screening and MES test. The compounds were synthesized under controlled conditions by the reaction of the substituted anilines with sodium nitrite, followed by the reaction with cyanoacetamide, substituted urea, ethanol, and water. The final compounds (5a-d; 6a-d) were tested for antiepileptic activity by in-silico screening targeting N-Methyl D-Aspartate glutamate receptor (PDB ID:5IPV). The screened compounds are also evaluated by in vivo test (MES) by taking phenytoin as a standard drug. The results of the whole study were satisfactory with the yield of the compounds in the range of 88% to 96%. The results of in- silico, screening showed that compounds 6a and 6c have far more binding energy compared with standard phenytoin (6a -7.5 Kcal/mol. ; 6c -7.6 Kcal/mol. and Phenytoin -6.5 Kcal/mol.). The TD50 values of synthesized compounds (6a-6d) are observed to be significantly higher than those of standard phenytoin. The PI values of several synthetic compounds (6a and 6c) were found to be higher (55.8% and 58.0%) than the current antiepileptic medicine phenytoin (55.6%), demonstrating the synthesized compound's safety potential.

Agrypnia excitata: a clinical biomarker of acute relapse in anti-NMDAr encephalitis.

Sleep disorders have been described in anti-NMDAr encephalitis including insomnia, hypersomnia, narcolepsy, and sleep-disordered breathing. A patient presented with typical features of anti-NMDAr encephalitis associated with a right ovarian teratoma. After two months of clinical improvement with immunotherapy, the patient deteriorated. A 24-hour video EEG-polysomnography revealed a severe sleep quantity deficit, a total destruction of sleep architecture consisting of short clusters of N1 and rapid eye movement sleep stages, associated with motor and autonomic hyperactivity. These features were consistent with agrypnia excitata and were associated with disease reactivation due to a left ovarian teratoma. A new course of immunotherapy and surgery improved clinical symptoms and normalized sleep patterns. Agrypnia excitata, the most severe form of status dissociatus, was a sleep biomarker of disease relapse in this patient. Polysomnographic studies in the acute phase of anti-NMDAr encephalitis are lacking and are needed to better understand the evolution of sleep patterns.

MRI findings in autoimmune encephalitis.

Autoimmune encephalitis encompasses a spectrum of conditions characterized by distinct clinical features and magnetic resonance imaging (MRI) findings. Here, we review the literature on acute MRI changes in the most common autoimmune encephalitis variants. In N-methyl-D-aspartate (NMDA) receptor encephalitis, most patients have a normal MRI in the acute stage. When lesions are present in the acute stage, they are typically subtle and non-specific white matter lesions that do not correspond with the clinical syndrome. In some NMDA receptor encephalitis cases, these T2-hyperintense lesions may be indicative of an NMDA receptor encephalitis overlap syndrome with simultaneous co-existence of multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Encephalitis with leucine-rich glioma-inactivated 1 (LGI1)-, contactin-associated protein-like 2 (CASPR2)- or glutamic acid decarboxylase (GAD)- antibodies typically presents as limbic encephalitis (LE) with unilateral or bilateral T2/fluid attenuated inversion recovery (FLAIR) hyperintensities in the medial temporal lobe that can progress to hippocampal atrophy. Gamma aminobutyric acid-B (GABA-B) receptor encephalitis also often shows such medial temporal hyperintensities but may additionally involve cerebellar lesions and atrophy. Gamma aminobutyric acid-A (GABA-A) receptor encephalitis features multifocal, confluent lesions in cortical and subcortical areas, sometimes leading to generalized atrophy. MRI is unremarkable in most patients with immunoglobulin-like cell adhesion molecule 5 (IgLON5)-disease, while individual case reports identified T2/FLAIR hyperintense lesions, diffusion restriction and atrophy in the brainstem, hippocampus and cerebellum. These findings highlight the need for MRI studies in patients with suspected autoimmune encephalitis to capture disease-specific changes and to exclude alternative diagnoses. Ideally, MRI investigations should be performed using dedicated autoimmune encephalitis imaging protocols. Longitudinal MRI studies play an important role to evaluate potential relapses and to manage long-term complications. Advanced MRI techniques and current research into imaging biomarkers will help to enhance the diagnostic accuracy of MRI investigations and individual patient outcome prediction. This will eventually enable better treatment decisions with improved clinical outcomes.

Olanzapine vs. magnesium valproate vs. lamotrigine in anti-N-methyl-D-aspartic acid receptor encephalitis: a retrospective study.

BACKGROUND: This study aimed to compare the impact of olanzapine, magnesium valproate, and lamotrigine as adjunctive treatments for anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. And it is expected to add supporting points related to the rebalance of neurotransmitters in the brain through adjuvant therapy in the clinical management of anti-NMDAR encephalitis. METHODS: This retrospective study included patients diagnosed with anti-NMDAR encephalitis who received standardized immunotherapy at Hunan Brain Hospital between January 2018 and December 2020. RESULTS: Compared to the olanzapine group, both the magnesium valproate and lamotrigine groups showed lower scores on the positive and negative symptom scale (PANSS) total score after 3 weeks of treatment (all P < 0.05). The Montreal Cognitive Assessment Scale (MoCA) scores in the magnesium valproate and lamotrigine groups were significantly higher than in the olanzapine group after 3 weeks and 3 months of treatment (all P < 0.05). After 3 months of treatment, the proportions of patients with a modified Rankin scale score (mRS) of 0-1 in the magnesium valproate and lamotrigine groups were significantly higher than in the olanzapine group (all P < 0.05). The electroencephalogram (EEG) abnormality ranks at 3 months were significantly lower in the magnesium valproate and lamotrigine groups compared with the olanzapine group (all P < 0.05). Furthermore, the Glx/Cr ratio significantly decreased after 3 months of treatment (all P < 0.05) in the magnesium valproate and lamotrigine groups, while the Glx/Cr ratio in the olanzapine group showed no significant change (P > 0.05). CONCLUSION: Compared with olanzapine, the addition of magnesium valproate or lamotrigine to immunotherapy might be associated with a lower PANSS score, higher MoCA score, and lower mRS score. The improvement of neurological functions and cognitive function may be related to the decreased Glx/Cr ratio.

Ofatumumab treatment for severe refractory anti-NMDAR encephalitis: A case series.

Rituximab is recommended as the preferred second-line immunotherapy for autoimmune encephalitis (AE). However, Ofatumumab (OFA), a novel fully human anti-CD20 antibody, has been reported infrequently in patients with AE. Among the various forms of AE, anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is the most common and severe. This study presents three cases of severe anti-NMDAR encephalitis treated with OFA following the failure of first-line immunotherapy. The results indicated that the patients experienced no significant adverse reactions after receiving OFA, and their clinical symptoms improved markedly within one week of treatment. One month post-treatment with OFA, scores on the Glasgow Coma Scale (GCS) and the Barthel Index of Activities of Daily Living (Barthel-ADL) increased, while scores on the modified Rankin Scale (mRS), Clinical Assessment Scale in Autoimmune Encephalitis (CASE), and Paroxysmal Sympathetic Hyperactivity Assessment Measure (PSH-AM) decreased. During the three-month and six-month follow-up periods, patients exhibited further symptomatic improvement, suggesting that OFA is a safe and effective treatment option for anti-NMDAR encephalitis. These findings propose a novel therapeutic strategy for severe refractory anti-NMDAR encephalitis.

Abnormal large-scale resting-state functional networks in anti-N-methyl-D-aspartate receptor encephalitis.

Background: Patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis often experience severe symptoms. Resting-state functional MRI (rs-fMRI) has revealed widespread impairment of functional networks in patients. However, the changes in information flow remain unclear. This study aims to investigate the intrinsic functional connectivity (FC) both within and between resting-state networks (RSNs), as well as the alterations in effective connectivity (EC) between these networks. Methods: Resting-state functional MRI (rs-fMRI) data were collected from 25 patients with anti-NMDAR encephalitis and 30 healthy controls (HCs) matched for age, sex, and educational level. Changes in the intrinsic functional connectivity (FC) within and between RSNs were analyzed using independent component analysis (ICA). The functional interaction between RSNs was identified by granger causality analysis (GCA). Results: Compared to HCs, patients with anti-NMDAR encephalitis exhibited lower performance on the Wisconsin Card Sorting Test (WCST), both in terms of correct numbers and correct categories. Additionally, these patients demonstrated decreased scores on the Montreal Cognitive Assessment (MoCA). Neuroimaging studies revealed abnormal intra-FC within the default mode network (DMN), increased intra-FC within the visual network (VN) and dorsal attention network (DAN), as well as increased inter-FC between VN and the frontoparietal network (FPN). Furthermore, aberrant effective connectivity (EC) was observed among the DMN, DAN, FPN, VN, and somatomotor network (SMN). Conclusion: Patients with anti-NMDAR encephalitis displayed noticeable deficits in both memory and executive function. Notably, these patients exhibited widespread impairments in intra-FC, inter-FC, and EC. These results may help to explain the pathophysiological mechanism of anti-NMDAR encephalitis.

Anti-N-methyl-D-aspartate Receptor Encephalitis in Turner Syndrome with 45,X/46,X,idic(X)(p11.4) Mosaics.

A 46-year-old woman with Turner syndrome (TS) (45,X/46,X,idic (X) (p11.4) mosaic) presented with a fever, unresponsiveness, hyperhidrosis, and rigidity approximately one month after episodes of confusion and suicide attempts, prompting a diagnosis of schizophrenia. Cerebrospinal fluid (CSF) showed mild hypercellularity with oligoclonal bands. Brain and abdominal magnetic resonance imaging showed no abnormalities. Bizarre upper-extremity movements and spasms followed the trial administration of acyclovir, and autoimmune encephalitis was suspected. Intensive immunotherapy was initiated, and the symptoms improved. Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis was diagnosed based on the presence of anti-NMDAR antibodies in her spinal fluid. This case represents a rare presentation of anti-NMDAR encephalitis in TS, which is susceptible to autoimmune disease complications.

The familiarity of Romanian psychiatrists with anti-N-methyl-D-aspartate receptor encephalitis: findings from a web-based survey study.

Background and aims: Psychiatrists are often the first to be consulted in patients with anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis. Thus, they need to be aware of clinical features, differential diagnoses, and treatment options for this condition. In this study, we aimed to investigate the familiarity of Romanian psychiatrists with anti-NMDAR encephalitis. Methods: We recruited psychiatrists from Romania and conducted a cross-sectional observational study by using a web-based survey. Results: The survey was completed by 111 psychiatrists, of whom 47 (42.34%) were specialists, while 64 (57.66%) were trainees. The median length of training for specialists was ten years (interquartile range - IQR 9.5), while for trainees it was 2.5 years (IQR 3). In total, 31 (27.93%) psychiatrists encountered a case of anti-NMDAR encephalitis, with no significant difference between specialists and trainees. 31 (27.93%) psychiatrists were either unaware of the disorder or only knew its name, while 77 (69.37%) had knowledge of an outline of it. Only 3 (2.7%) psychiatrists had comprehensive knowledge of the disorder. Respondents with a higher awareness level had undergone significantly longer training (p=0.014). Unsurprisingly, having encountered a case significantly influenced awareness levels (p<0.001). There were no significant differences between specialists and trainees regarding specific knowledge about anti-NMDAR encephalitis. However, higher awareness levels and having encountered a case significantly influenced answer accuracy for questions regarding psychiatric presentation and epidemiological features. Conclusions: Our study indicates that Romanian psychiatrists have suboptimal knowledge of anti-NMDAR encephalitis, highlighting the need for improved awareness of this disorder.

Misalignment of Circadian Rhythms in Diet-Induced Obesity.

The biological clocks of the circadian timing system coordinate cellular and physiological processes and synchronize them with daily cycles. While the central clock in the suprachiasmatic nucleus (SCN) is mainly synchronized by the light/dark cycles, the peripheral clocks react to other stimuli, including the feeding/fasting state, nutrients, sleep-wake cycles, and physical activity. During the disruption of circadian rhythms due to genetic mutations or social and occupational obligations, incorrect arrangement between the internal clock system and environmental rhythms leads to the development of obesity. Desynchronization between the central and peripheral clocks by altered timing of food intake and diet composition leads to uncoupling of the peripheral clocks from the central pacemaker and to the development of metabolic disorders. The strong coupling of the SCN to the light-dark cycle creates a situation of misalignment when food is ingested during the "wrong" time of day. Food-anticipatory activity is mediated by a self-sustained circadian timing, and its principal component is a food-entrainable oscillator. Modifying the time of feeding alone greatly affects body weight, whereas ketogenic diet (KD) influences circadian biology, through the modulation of clock gene expression. Night-eating behavior is one of the causes of circadian disruption, and night eaters have compulsive and uncontrolled eating with severe obesity. By contrast, time-restricted eating (TRE) restores circadian rhythms through maintaining an appropriate daily rhythm of the eating-fasting cycle. The hypothalamus has a crucial role in the regulation of energy balance rather than food intake. While circadian locomotor output cycles kaput (CLOCK) expression levels increase with high-fat diet-induced obesity, peroxisome proliferator-activated receptor-alpha (PPARα) increases the transcriptional level of brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1) in obese subjects. In this context, effective timing of chronotherapies aiming to correct SCN-driven rhythms depends on an accurate assessment of the SCN phase. In fact, in a multi-oscillator system, local rhythmicity and its disruption reflects the disruption of either local clocks or central clocks, thus imposing rhythmicity on those local tissues, whereas misalignment of peripheral oscillators is due to exosome-based intercellular communication.Consequently, disruption of clock genes results in dyslipidemia, insulin resistance, and obesity, while light exposure during the daytime, food intake during the daytime, and sleeping during the biological night promote circadian alignment between the central and peripheral clocks. Thus, shift work is associated with an increased risk of obesity, diabetes, and cardiovascular diseases because of unusual eating times as well as unusual light exposure and disruption of the circadian rhythm.

Serum neuron-specific enolase can predict the severity and outcome of anti-N-methyl-D-aspartate receptor encephalitis.

BACKGROUND: Little is known about the association between serum neuron-specific enolase (NSE) concentration and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. This study aims to investigate if serum NSE concentration is related to the clinical features of anti-NMDAR encephalitis. METHODS: Serum NSE levels were detected in 58 anti-NMDAR encephalitis cases, 58 matched healthy controls and 58 matched disease controls. Demographic features, clinical symptoms, cerebrospinal fluid parameters and brain MRI indexes of the cases were evaluated. RESULTS: Serum NSE concentrations were significant higher in case group than those in healthy controls and disease controls (both p < 0.001). Serum NSE concentrations in patients with mRS≥3 one year after onset were obviously higher than in those with mRS<3 (p < 0.001). Patients with status epilepticus or central hypoventilation had higher serum NSE levels than those without (p = 0.003 and p = 0.006). Serum NSE concentrations in cases with brain lesions or brain atrophy were significant higher than in those without (p = 0.001 and p < 0.001, respectively). Serum NSE concentrations were found to be significant higher in cases with limited response to treatment compared to those with favourable therapy outcomes (p < 0.001). Spearman's correlation analysis showed a significant positive association between serum NSE concentration and mRS score at the most critical time (max mRS) (r = 0.575, p < 0.001) and one year after onset (r = 0.705, p < 0.001). Cox regression results reflected that high serum NSE level was an independent predictor of poor prognosis in anti-NMDAR encephalitis group (p = 0.001), and the ROC curve threshold value was 15.72 ng/ml. CONCLUSIONS: Serum NSE concentrations in anti-NMDAR encephalitis cases are higher than those in controls. It can be used to predict the brain damage degree and prognosis of anti-NMDAR encephalitis cases.

A Dose-Finding, Biomarker Validation, and Effectiveness Study of Transcranial Magnetic Stimulation for Adolescents With Depression.

OBJECTIVE: Research and clinical application of transcranial magnetic stimulation (TMS) for adolescents with major depressive disorder (MDD) has advanced slowly. Significant gaps persist in our understanding of optimized, age-specific protocols and dosing strategies. This study aimed to compare the clinical effects of 1 Hz versus 10 Hz TMS regimens and examine a biomarker-informed treatment approach with glutamatergic intracortical facilitation (ICF). METHOD: Participants with moderate-to-severe symptoms of MDD were randomized to 30 sessions of left prefrontal 1 Hz or 10 Hz TMS, stratified by baseline ICF measures. The primary clinical outcome measure was the Children's Depression Rating Scale, Revised (CDRS-R). The CDRS-R and ICF biomarker were collected weekly. RESULTS: Forty-one participants received either 1 Hz (n = 22) or 10 Hz (n = 19) TMS treatments. CDRS-R scores improved compared to baseline in both 1 Hz and 10 Hz groups. For participants with low ICF at baseline, the overall least squares means of CDRS-R scores over the 6-week trial showed that depressive symptom severity was lower for the group treated with 1 Hz TMS than for those who received 10 Hz TMS. There were no significant changes in weekly ICF measurements across the 6 weeks of TMS treatment. CONCLUSION: Low ICF may reflect optimal glutamatergic N-methyl-d-aspartate (NMDA) receptor activity that facilitates the therapeutic effect of 1 Hz TMS through long-term depression-like mechanisms on synaptic plasticity. The stability of ICF suggests that it is a tonic, trait-like measure of NMDA receptor-mediated neurotransmission, with potential utility to inform parameter selection for therapeutic TMS in adolescents with MDD.

Oral and Dental Pain Management.

Pain has been defined as an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage. Pets often experience the same pain as people; however, dental pain is often overlooked, discounted, or unseen/hidden in patients, as the inability to communicate does not negate the possibility that a human or a nonhuman animal experiences pain. This article discusses types of pain and the methods and medications available to treat and prevent oral pain.

Neuroactive Kynurenines as Pharmacological Targets: New Experimental Tools and Exciting Therapeutic Opportunities.

Both pre-clinical and clinical studies implicate functional impairments of several neuroactive metabolites of the kynurenine pathway (KP), the major degradative cascade of the essential amino acid tryptophan in mammals, in the pathophysiology of neurological and psychiatric diseases. A number of KP enzymes, such as tryptophan 2,3-dioxygenase (TDO2), indoleamine 2,3-dioxygenases (IDO1 and IDO2), kynurenine aminotransferases (KATs), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilate oxidase (3-HAO), and quinolinic acid phosphoribosyltransferase (QPRT), control brain KP metabolism in health and disease and are therefore increasingly considered to be promising targets for the treatment of disorders of the nervous system. Understanding the distribution, cellular expression, and regulation of KP enzymes and KP metabolites in the brain is therefore critical for the conceptualization and implementation of successful therapeutic strategies. Significance Statement Studies have implicated the kynurenine pathway of tryptophan in the pathophysiology of neurological and psychiatric diseases. Key enzymes of the kynurenine pathway regulate brain metabolism in both health and disease, making them promising targets for treating these disorders. Therefore, understanding the distribution, cellular expression, and regulation of these enzymes and metabolites in the brain is critical for developing effective therapeutic strategies. In this review, we endeavor to describe these processes in detail.

Efficacy of Fluoxetine and (R,S) Ketamine in Attenuating Conditioned Fear Behaviors in Male Mice.

Post-traumatic stress disorder (PTSD) is caused by exposure to a traumatic or stressful event. Symptoms related to this disorder include persistent re-experiencing of memories and fear generalization. Current pharmacological treatments for PTSD are insufficient, with fewer than 30% of patients reporting symptom remission. This study aims to determine the efficacy of acute (R,S) ketamine and chronic fluoxetine (FLX) in reducing fear memory and fear generalization. In rodents, fear conditioning (FC) is commonly used in the literature to induce behaviors related to symptoms of PTSD, and the open field test (OFT) can assess anxiety and fear generalization behaviors during the exploration of a novel environment. In this study, FC consisted of a white noise cue stimulus and four inescapable foot shocks. Treatments began 4 hours after FC. Fear and anxiety behaviors were recorded during re-exposure to the FC stimuli at 24 hours and 2 weeks. The OFT was conducted one day before the last FC re-exposure. Results support the combined use of acute ketamine and chronic FLX as a treatment for reducing behaviors indicative of fear memory during re-exposure at 2 weeks, but not behaviors indicative of anxiety and fear generalization in the OFT. FLX alone was most effective in reducing behaviors related to fear generalization. This study contributes to the existing literature on pharmacological treatment for fear and anxiety behaviors relating to fear memory and fear generalization. Continued research is necessary to replicate results, optimize treatment protocols, and investigate the molecular adaptations to trauma and treatment. Significance Statement Up to 6% of people in the United States will develop PTSD within their lifetime, and less than half of those individuals will find relief from their symptoms given the current therapeutic options. This study offers preliminary support for the efficacy of ketamine and FLX in reducing PTSD-like behaviors induced by fear-conditioning in mice. Compared to current standard treatments, results indicate the potential for a more effective therapeutic option for those with stress-related disorders, such as PTSD.

Activation of astrocytic NMDA receptors counteracted Aß-induced reduction of BDNF and elevation of GFAP and complement 3 in the hippocampal astrocytes.

N-methyl-D-aspartate receptors (NMDARs) play a crucial role in mediating Amyloid-ß (Aß) synaptotoxicity. Our previous studies have demonstrated an opposite (neuroprotection and neurotoxicity) effect of activating astrocytic and neuronal NMDARs with higher dose (10 µM) of NMDA, an agonist of NMDARs. By contrast, activating neuronal or astrocyitc NMDARs with lower dose (1 µM) of NMDA both exerts neuroprotective effect in Aß-induced neurotoxicity. However, the underlying mechanism of activating astrocytic NMDARs with lower dose of NMDA to protect against Aß neurotoxicity remains unclear. Based on our previous related work, in this study, using a co-cultured cell model of primary hippocampal neurons and astrocytes, we further investigated the possible factors involved in 1 µM of NMDA activating astrocytic NMDARs to oppose Aß-induced synaptotoxicity. Our results showed that activation of astrocytic NMDARs by 1 µM NMDA rescued Aß-induced reduction of brain-derived neurotrophic factor (BDNF), and inhibited Aß-induced increase of GFAP, complement 3 (C3) and activation of NF-κB. Furthermore, blockade of astrocytic GluN2A with TCN201 abrogated the ability of 1 µM NMDA to counteract the effects of Aß decreasing BDNF, and increasing GFAP, C3 and activation of NF-κB. These findings suggest that activation of astrocytic NMDARs protect against Aß-induced synaptotoxicity probably through elevating BDNF and suppressing GFAP and C3. Our present research provides valuable insights for elucidating the underlying mechanism of astrocytic NMDARs activation resisting the toxic effects of Aß.

Chaihu Guizhi Decoction prevents cognitive, memory impairments and sensorimotor gating deficit induced by N-methyl-d-aspartate receptor antibody in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Anti-NMDAR encephalitis is one of the most common types of autoimmune encephalitis, primarily presenting with prodromal symptoms, such as fever and headache, followed by a range of neurological and psychiatric symptoms. Chaihu Guizhi Decoction (CGD), a traditional Chinese medicine formulated by Zhang Zhongjing in the Eastern Han Dynasty, has been effectively used in clinical practice to treat the symptoms of Taiyang and Shaoyang disorders, including fever, headache, and psychiatric disorders. AIM OF THE STUDY: To demonstrate the protective effects of CGD in an animal model of anti-NMDAR encephalitis and explore the potential mechanisms involved. MATERIALS AND METHODS: UHPLC-HRMS was used to identify CGD's chemical components and serum metabolomic profiles. Network pharmacology and molecular docking were performed to predict potential targets of CGD for the treatment of anti-NMDAR encephalitis. The effect of CGD on anti-NMDAR encephalitis was evaluated using a mouse model induced by patients' antibodies. Behavioral tests were performed to assess cognitive impairment and schizophrenia-like behaviors. The effect of CGD on the cell-surface NMDAR GluN1 subunit in cultured neurons treated with patient antibodies was detected by immunofluorescence. Golgi staining was used to observe morphological changes in hippocampal dendrites. The expression of NMDAR-interacting proteins and various neuroreceptors in the hippocampus were examined to validate the targets predicted using network pharmacology and molecular docking. RESULTS: CGD alleviated cognitive, memory, and sensorimotor gating deficits in mice treated with anti-NMDAR encephalitis patients' antibodies. Further experiments demonstrated the effect of CGD in preventing NMDAR reduction both in vitro and in vivo. Meanwhile, CGD regulated NMDAR-interacting proteins and dopamine receptors but did not affect hippocampal dendritic morphology and synaptic density. Additionally, CGD modifies metabolic pathways associated with anti-NMDAR encephalitis and other neurological and psychiatric disorders. CONCLUSIONS: CGD exhibited protective effects against anti-NMDAR encephalitis by mitigating the antibody-induced reduction in NMDAR and NMDAR-interacting proteins.

Clinical characteristics and outcomes of patients with antibody-related autoimmune encephalitis presenting with disorders of consciousness: A prospective cohort study.

OBJECTIVE: To explore the clinical characteristics, short- and long-term functional outcomes, and risk factors for antibody-related autoimmune encephalitis (AE) in patients with disorders of consciousness (DoC). METHODS: Clinical data were collected from AE patients admitted to Xuanwu Hospital of Capital Medical University from January 2012 to December 2021, and patients were followed up for up to 24 months after immunotherapy. RESULTS: A total of 312 patients with AE were included: 197 (63.1%) with anti-NMDAR encephalitis, 71 (22.8%) with anti-LGI1 encephalitis, 20 (6.4%) with anti-GABAbR encephalitis, 10 (3.2%) with anti-CASPR2 encephalitis, 10 (3.2%) with anti-GAD65 encephalitis, and 4 (1.3%) with anti-AMPAR2 encephalitis. Among these patients, 32.4% (101/312) presented with DoC, and the median (interquartile range, IQR) time to DoC was 16 (7.5, 32) days. DoC patients had higher rates of various clinical features of AE (p < .05). DoC was associated with elevated lumbar puncture cerebrospinal fluid (CSF) pressure, CSF leukocyte count, and specific antibody titer (p < .05). A high percentage of patients in the DoC group had a poor prognosis at discharge and at 6 months after immunotherapy (p < .001), but no significant difference in prognosis was noted between the DoC group and the non-DoC group at 12 and 24 months after immunotherapy. Dyskinesia (OR = 3.266, 95% CI: 1.550-6.925, p = .002), autonomic dysfunction (OR = 5.871, 95% CI: 2.574-14.096, and p < .001), increased CSF pressure (OR = 1.007, 95% CI: 1.001-1.014, p = .046), and modified Rankin scale (mRS) score ≥3 at the initiation of immunotherapy (OR = 7.457, 95% CI: 3.225-18.839, p < .001) were independent risk factors for DoC in AE patients. CONCLUSION: DoC is a relatively common clinical symptom in patients with AE, especially critically ill patients. Despite requiring longer hospitalization, DoC mostly improves with treatment of the primary disease and has a good long-term prognosis after aggressive life support and combination immunotherapy.

Post-Herpetic Anti-NMDAR Encephalitis in Denmark: Current Status and Future Challenges.

It is well known that N-methyl-D-aspartate receptor encephalitis (NMDARE) can be triggered by infectious encephalitis such as herpes simplex virus 1 encephalitis (HSE). However, the incidence of post-HSE NMDARE in Denmark is unknown. We reviewed literature cases and compared these to retrospectively identified cases of post-HSE NMDARE in Denmark, using a national cohort database of autoimmune encephalitis (AE) and two regional databases of infectious encephalitis patients. We identified 80 post-HSE NMDARE cases in the literature, 66% being children, who more often presented movement disorders, decreased consciousness, and sleep disturbances compared to adults. Eight patients with post-HSE NMDARE were identified from the national cohort database of AE, none being children. Forty-four HSE patients were identified from the regional infectious encephalitis databases. Of these, 16 (36%) fulfilled the Graus criteria for probable/definite NMDARE, and eight (18%) presented a prolonged/relapsing disease course. Ten (23%) were tested for AE during hospitalization. Six (14%) had leftover cerebrospinal fluid available for retrospective autoantibody testing. One out of these six patients (17%) harbored NMDARE antibodies. Thus, in total, nine post-HSE NMDARE patients have been identified in Denmark from 2009 to 2021. Comparing the adult Danish patients to the literature, Danish patients were older, but the clinical phenotype and paraclinical findings were similar. Overall, the incidence of adult post-HSE NMDARE in the Region of Southern Denmark was 0.17 per million people per year and only 7% of adult HSE patients in the region were diagnosed with post-HSE NMDARE. Our findings suggest that adult patients are still underdiagnosed and the absence of pediatric cases diagnosed with post-HSE NMDARE in Denmark is highly concerning.

Molecular, Pathophysiological, and Clinical Aspects of Corticosteroid-Induced Neuropsychiatric Effects: From Bench to Bedside.

Corticosteroids are frequently prescribed across medical disciplines, yet they are associated with various adverse effects, including neuropsychiatric symptoms, documented since their introduction over 60 years ago. The cellular mechanisms underlying neuropsychiatric symptoms are complex and somewhat obscure, involving multiple pathways. Notably, they include changes in excitability, cellular death of hippocampal and striatal neurons, and increased inflammation and oxidative stress. Clinical presentation varies, encompassing affective disorders (anxiety, euphoria, depression), psychotic episodes, and cognitive deficits. It is crucial to note that these manifestations often go unnoticed by treating physicians, leading to delayed detection of severe symptoms, complications, and underreporting. Discontinuation of corticosteroids constitutes the cornerstone of treatment, resolving symptoms in up to 80% of cases. Although the literature on this topic is scant, isolated cases and limited studies have explored the efficacy of psychotropic medications for symptomatic control and prophylaxis. Pharmacological intervention may be warranted in situations where corticosteroid reduction or withdrawal is not feasible or beneficial for the patient.

Targeting NMDA receptors with an antagonist is a promising therapeutic strategy for treating neurological disorders.

Glutamate activates the NMDARs, significantly affecting multiple processes such as learning, memory, synaptic integration, and excitatory transmission in the central nervous system. Uncontrolled activation of NMDARs is a significant contributor to synaptic dysfunction. Having a properly functioning NMDAR and synapse is crucial for maintaining neuronal communication. In addition, the dysfunction of NMDAR and synapse function could contribute to the development of neurological disorders at the neuronal level; hence, targeting NMDARs with antagonists in the fight against neurological disorders is a promising route. Recently published results from the animal study on different kinds of brain diseases like stroke, epilepsy, tinnitus, ataxia, Alzheimer's disease, Parkinson's disease, and spinal cord injury have demonstrated promising therapeutic scopes. Several NMDA receptor antagonists, such as memantine, MK801, ketamine, ifenprodil, gacyclidine, amantadine, agmatine, etc., showed encouraging results against different brain disease mouse models. Given the unique expression of different subunits of the well-organized NMDA receptor system by neurons. It could potentially lead to the development of medications specifically targeting certain receptor subtypes. For a future researcher, conducting more targeted research and trials is crucial to fully understand and develop highly specific medications with good clinical effects and potential neuroprotective properties.