CNS Neuroscience & Therapeutics

Background The presence of glioma stem cells (GSCs) and the occurrence of mesenchymal phenotype transition contribute to the miserable prognosis of glioblastoma (GBM). Cellular communication network factor 1 (CCN1) is upregulated within various malignancies and associated with cancer development and progression, while the implications of CCN1 in the phenotype transition and tumorigenicity of GSCs remain unclear. Methods Data for bioinformatic analysis were obtained from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. A range of primary GBM and GSC cell models were then used to demonstrate the regulatory role of CCN1 via the phenotype validation, tumor sphere formation assays, extreme limiting dilution assays (ELDA), and transwell assays. To screen out the downstream signaling pathway, we employed high‐throughput RNA‐seq. Intracranial xenograft GSC mouse models were used to investigate the role of CCN1 in vivo. Results Among the CCN family members, CCN1 was highly expressed in MES‐GBM/GSCs and was correlated with a poor prognosis. Both in vitro and in vivo assays indicated that knockdown of CCN1 in MES‐GSCs reduced the tumor stemness, proliferation, invasion, and tumorigenicity, whereas CCN1 overexpression in PN‐GSCs exhibited the opposite effects. Mechanistically, CCN1 triggered the FAK/STAT3 signaling in autocrine and paracrine manners to upregulate the expression of S100A8. Knockdown of S100A8 inactivated NF‐κB/p65 pathway and significantly suppressed the tumorigenesis of MES‐GSCs. Conclusion Our findings reveal that CCN1 may be an important factor in the enhanced invasiveness and MES phenotype transition of GSCs and highlight the potential to target CCN1 for treating GBM.

Aims To investigate whether pleiotrophin (PTN) overexpression influences ethanol consumption during adolescence and its effects on glial responses, neurogenesis, and perineuronal nets (PNNs) in the mouse hippocampus. Methods Male and female adolescent transgenic mice with elevated PTN levels (Ptn‐Tg) and controls underwent an intermittent access to ethanol (IAE) 2‐bottle choice protocol. Ethanol consumption, PTN levels, neurogenesis, and glial responses were measured in the hippocampus. Immunohistochemistry was used to assess changes in new neurons, microglial and astrocyte populations, and PNNs. Results Ptn‐Tg mice consumed significantly less ethanol compared to controls, irrespective of sex. Chronic alcohol exposure reduced PTN levels in the hippocampus. PTN overexpression decreased the number of new neurons in the dentate gyrus (DG) and prevented ethanol‐induced microglial activation. Ptn‐Tg mice had significantly more astrocytes and fewer PNNs, with a higher percentage of parvalbumin (PV) positive cells surrounded by PNNs under basal conditions. However, ethanol drastically reduced the number of PV+ cells in the DG of Ptn‐Tg mice, despite the presence of PNNs. Conclusion PTN overexpression reduces adolescent ethanol consumption and influences ethanol‐induced effects on hippocampal neurogenesis, glial responses, and PNN remodeling. These findings underscore the importance of PTN in modulating alcohol‐induced neurotoxicity.

Background Microglia/macrophages, as pivotal immune cells in the central nervous system (CNS), play a critical role in neuroinflammation associated with ischemic brain injury. Targeting their activation through pharmacological interventions represents a promising strategy to alleviate neurological deficits, thereby harboring significant implications for the prevention and treatment of ischemic stroke. Ligusticum cycloprolactam (LIGc), a novel monomeric derivative of traditional Chinese medicine, has shown potential as a therapeutic agent; however, its specific role in cerebral ischemic injury remains unclear. Methods In vitro experiments utilized lipopolysaccharide (LPS)‐induced inflammation models of RAW264.7 cells and primary mouse microglia. In vivo studies employed LPS‐induced neuroinflammation models in mice and a transient middle cerebral artery occlusion (tMCAO) mouse model to evaluate the impact of LIGc on neuroinflammation and microglia/macrophage phenotypic alterations. Further elucidation of the molecular mechanisms underlying these effects was achieved through RNA‐Seq analyses. Results LIGc exhibited the capacity to attenuate LPS‐induced production of pro‐inflammatory markers in macrophages and microglia, facilitating their transition to an anti‐inflammatory phenotype. In models of LPS‐induced neuroinflammation and tMCAO, LIGc ameliorated pathological behaviors and neurological deficits while mitigating brain inflammation. RNA‐seq analyses revealed formyl peptide receptor 1 (FPR1) as a critical mediator of LIGc's effects. Specifically, FPR1 enhances the pro‐inflammatory phenotype of microglia/macrophages and inhibits their anti‐inflammatory response by upregulating NLR family pyrin domain protein 3 (NLRP3) inflammasomes, thus aggravating inflammatory processes. Conversely, LIGc exerts anti‐inflammatory effects by downregulating the FPR1/NLRP3 signaling axis. Furthermore, FPR1 overexpression or NLRP3 agonists reversed the effects of LIGc observed in this study. Conclusion Our findings suggest that LIGc holds promise in improving ischemic brain injury and neuroinflammation through modulation of microglia/macrophage polarization. Mechanistically, LIGc attenuates the pro‐inflammatory phenotype and promotes the anti‐inflammatory phenotype by targeting the FPR1/NLRP3 signaling pathway, ultimately reducing inflammatory responses and mitigating neurological damage.

Brain‐derived neurotrophic factor (BDNF), which is primarily expressed in the brain and nervous tissues, is the most abundant neurotrophic factor in the adult brain. BDNF serves not only as a major neurotrophic signaling agent in the human body but also as a crucial neuromodulator. Widely distributed throughout the central nervous system (CNS), both BDNF and its receptors play a significant role in promoting neuronal survival and growth, thereby exerting neuroprotective effects. It is further considered as a guiding medium for the functionality and structural plasticity of the CNS. Increasingly, research has indicated the critical importance of BDNF in understanding human diseases. Activation of intracellular signaling pathways such as the mitogen‐activated protein kinase pathway, phosphatidylinositol 3‐kinase/protein kinase B/mammalian target of rapamycin pathway, and phospholipase C γ pathway by BDNF can all potentially enhance the growth, survival, proliferation, and migration of cancer cells, influencing cancer development. The loss of BDNF and its receptor, tropomyosin receptor kinase B, in signaling pathways is also associated with increased susceptibility to brain and heart diseases. Additionally, reduced BDNF levels in both the central and peripheral systems have been closely linked to various neurogenic diseases, including neuropathic pain and psychiatric disorders. As such, this review summarizes and analyzes the impact of BDNF on neurogenic diseases, cancer, and cardiovascular diseases. This study thereby aimed to elucidate its effects on these diseases to provide new insights and approaches for their treatment.

Aims To investigate the association between intraoperative hypotension and newly developed cerebral infarction in patients with aneurysmal subarachnoid hemorrhage (aSAH) undergoing aneurysm clipping or coiling. Methods The patients who had emergent clipping/coiling procedures for aSAH under general anesthesia were included. The major exposure was mean arterial pressure (MAP) below different absolute or relative thresholds characterized by area under curve (AUC), duration, and time‐weighted average (TWA) value. The outcome was newly developed cerebral infarction. The associations between MAP and newly developed cerebral infarction were adjusted by other risk factors. Odds ratio and 95% confidence interval were used to present the statistical difference. Results A total of 1205 patients were included in the analysis. Of these, 260 patients (21.6%) developed new cerebral infarctions assessed by computed tomography. Patients with newly developed cerebral infarction had higher incidence of modified Fisher Scale (mFS) score 3 to 4 (80.0 vs. 69.1%, p < 0.01) and longer duration of anesthesia (4.3 vs. 3.9 h, p < 0.01). In the multivariate model, the AUC‐MAP (adjusted odds ratio: 1.00, 95% CI: 1.000 to 1.000, p = 0.02) and the TWA‐MAP (adjusted odds ratio: 1.01, 95% CI: 1.001 to 1.024, p = 0.04) of 20% decrease from baseline were closely associated with the newly developed cerebral infarction. Conclusions Mean arterial pressure decreased 20% from baseline value were independently associated with postoperative newly developed cerebral infarction in patients with aSAH.

Background Moyamoya disease (MMD) and moyamoya syndrome (MMS) are rare cerebrovascular conditions with unclear distinctions in clinical presentation and prognosis. Aim This study assessed potential differences between MMD and MMS patients using real‐world data on clinical manifestations, surgical outcomes, and stroke risk factors. Methods This multicenter, retrospective cohort study examined patients with MMD or MMS treated at three tertiary academic hospitals in China, with a mean follow‐up of 11.2 ± 3.1 years. Clinical differences were compared between MMD and MMS, and postoperative cerebrovascular events were compared between patients who underwent surgery and those with conservative management. Primary outcomes were postoperative ischemic and hemorrhagic strokes. Risk factors were evaluated via multivariate Cox regression analysis. Results Of the 2565 patients, 2349 had MMD and 216 had MMS. After 1:1 propensity‐score matching, no significant differences were observed between these two cohorts. Surgical patients had fewer cerebrovascular events than those who received conservative treatment (HR, 0.487; 95% CI, 0.334–0.711; p < 0.001). Preadmission modified Rankin scale scores > 2 (HR, 3.139; 95% CI, 1.254–7.857; p = 0.015) and periprocedural complications (HR, 8.666; 95% CI, 3.476–21.604; p < 0.001) were independent stroke risk factors in patients with MMD. Periprocedural complications (HR, 31.807; 95% CI, 10.916–92.684; p < 0.001) increased stroke risk in patients with MMS. Conclusions This real‐world study revealed substantial clinical overlap between MMD and MMS. Both groups derived significant benefits from surgical revascularization, suggesting distinction may not be necessary to guide surgical management decisions. Optimizing preoperative status and preventing periprocedural complications may improve outcomes in these rare cerebrovascular conditions. Trial Registration This study has been registered in the Chinese Clinical trial registry (registration number: ChiCTR2200064160)

Brain‐derived neurotrophic factor (BDNF) is a neurotrophin, acting as a neurotrophic signal and neuromodulator in the central nervous system (CNS). BDNF is synthesized from its precursor proBDNF within the CNS and peripheral tissues. Through activation of NTRK2/TRKB (neurotrophic receptor tyrosine kinase 2), BDNF promotes neuronal survival, synaptic plasticity, and neuronal growth, whereas it inhibits microglial activation and the release of pro‐inflammatory cytokines. BDNF is dysregulated in different neurodegenerative diseases and depressions. However, there is a major controversy concerning BDNF levels in the different stages of multiple sclerosis (MS). Therefore, this review discusses the potential role of BDNF signaling in stages of MS, and how BDNF modulators affect the pathogenesis and outcomes of this disease.

Aim Hyperlipidemia is a common comorbidity of stroke patients, elucidating the mechanism that underlies the exacerbated ischemic brain injury after stroke with hyperlipidemia is emerging as a significant clinical problem due to the growing proportion of hyperlipidemic stroke patients. Methods Mice were fed a high‐fat diet for 12 weeks to induce hyperlipidemia. Transient middle cerebral artery occlusion was induced as a mouse model of ischemic stroke. Emx1Cre mice were crossed with Mef2cfl/fl mice to specifically deplete Mef2c in neurons. Results We reported that hyperlipidemia significantly aggravated neuronal necroptosis and exacerbated long‐term neurological deficits following ischemic stroke in mice. Mechanistically, Cflar, an upstream necroptotic regulator, was alternatively spliced into pro‐necroptotic isoform (CflarR) in ischemic neurons of hyperlipidemic mice. Neuronal Mef2c was a transcription factor modulating Cflar splicing and upregulated by hyperlipidemia following stroke. Neuronal specific Mef2c depletion reduced cerebral level of CflarR and cFLIPR (translated by CflarR), while mitigated neuron necroptosis and neurological deficits following stroke in hyperlipidemic mice. Conclusions Our study highlights the pathogenic role of CflarR splicing mediated by neuronal Mef2c, which aggravates neuron necroptosis following stroke with comorbid hyperlipidemia and proposes CflarR splicing as a potential therapeutic target for hyperlipidemic stroke patients.

Aims This study aimed to investigate the impact of the triglyceride‐glucose index (TyG index) on clinical consequences in individuals with large vascular occlusion (LVO)‐induced acute ischemic stroke (AIS) following endovascular treatment (EVT). Methods We conducted a single‐center retrospective cohort study, including AIS with LVO who underwent EVT. Patients were categorized into TyG index groups, calculated as “(fasting triglyceride [mg/dL] × fasting blood glucose [mg/dL]/2).” Clinical outcomes were assessed, including poor outcome (modified Rankin Scale [mRS] > 2 [3–6]) at 90 days, early neurological deterioration (END), symptomatic intracranial hemorrhage (sICH), and 90‐day mortality after EVT. Logistic regression and restricted cubic splines (RCS) were used to examine the relationship between the TyG index and clinical outcomes. Receiver operating characteristic (ROC) curve was constructed to evaluate the prognostic capacity of the TyG index. Results A total of 424 patients were included. Higher TyG levels were associated with worse functional outcome at 90 days (per unit: p = 0.006), sICH (per unit: p = 0.002, T3 versus T1: p = 0.004), and 90‐day mortality (T2 versus T1: p = 0.011, T3 versus T1: p = 0.029) in logistic regression. A RCS model revealed a linear association between the TyG index and poor outcome at 90 days, sICH, and 90‐day mortality (p for nonlinearity > 0.05). In ROC curve analysis, the traditional risk factors model (area under the curve [AUC]: 0.824, 95% CI: 0.784–0.859) was outperformed by the conventional risk factors + TyG index model (AUC: 0.845, 95% CI: 0.807–0.878) in predicting poor outcome (p = 0.021). Conclusion A higher TyG index is associated with worse clinical outcomes in LVO‐induced AIS patients after EVT. Additionally, the TyG index enhances risk prediction of traditional risk factors for poor outcome.

Introduction The centromedian nucleus (CM) of the thalamus is essential for arousal, attention, sensory processing, and motor control. Neuromodulation targeting CM dysfunction has shown efficacy in various neurological disorders. However, its individualized precise transcranial magnetic stimulation (TMS) remains unreported. Using resting‐state functional MRI, we mapped CM‐based functional connectivity (CM‐FC) to develop a personalized TMS scheme for neurological conditions. Methods We first analyzed the CM‐FC patterns of healthy subjects via 10 scanning sessions in three MRI scanners spanning two subject groups: one from the Human Connectome Project (n = 20, four sessions) dataset and the other from Hangzhou Normal University (n = 20, three sessions of 3 T MRI and three sessions of 1.5 T MRI). Pearson's correlation was used for CM‐FC evaluation. Then, we proposed an overlapping index ranging from 1 to 10, and group‐level clusters with the highest overlapping index located 4 cm beneath the scalp were identified. In the individual CM‐FC map, watershed image segmentation was used to obtain an individual cluster. The peak voxel with the highest FC value within the individual cluster was defined as a potential individualized target for future TMS. Results The spatial FC patterns were remarkably similar between the left and right CMs. CMs have widespread positive connectivity with cortical areas, including the sensorimotor cortex, supplementary motor area, middle frontal cortex, medial temporal cortex, and middle cingulate. Among the group‐level FC patterns of the left and right CMs, only the left CM had a group cluster in the left primary sensorimotor cortex (PSMC, cluster size = 51) with an overlapping index of 10, that is, 10 sessions showed significant CM‐FC. Conclusions The left PSMC exhibited reproducible FC with the left CM. The individual peak FC location in the left PSMC could be used as a TMS target for indirect modulation of CM activity and aid in the treatment of CM‐related neurological disorders.

Background The treatment of spinal cord injury (SCI) is usually ineffective, because neuroinflammatory secondary injury is an important cause of the continuous development of spinal cord injury, and microglial pyroptosis is an important step of neuroinflammation. Recently, Bmal1, a core component of circadian clock genes (CCGs), has been shown to play a regulatory role in various tissues and cells. However, it is still unclear whether Bmal1 regulates microglial pyroptosis after SCI. Methods In this study, we established an in vivo mouse model of SCI using Bmal1 knockout (KO) mice and wild‐type (WT) mice, and lipopolysaccharide (LPS)‐induced pyroptosis in BV2 cells as an in vitro model. A series of molecular and histological methods were used to detect the level of pyroptosis and explore the regulatory mechanism in vivo and in vitro respectively. Results Both in vitro and in vivo results showed that Bmal1 inhibited NLRP3 inflammasome activation and microglial pyroptosis after SCI. Further analysis showed that Bmal1 inhibited pyroptosis‐related proteins (NLRP3, Caspase‐1, ASC, GSDMD‐N) and reduced the release of IL‐18 and IL‐1β by inhibiting the NF‐κB /MMP9 pathway. It was important that NF‐κB was identified as a transcription factor that promotes the expression of MMP9, which in turn regulates microglial pyroptosis after SCI. Conclusions Our study initially identified that Bmal1 regulates the NF‐κB /MMP9 pathway to reduce microglial pyroptosis and thereby reduce secondary spinal cord injury, providing a new promising therapeutic target for SCI.

Background Depression, a widespread mental disorder, presents significant risks to both physical and mental health due to its high rates of recurrence and suicide. Currently, single‐target antidepressants typically alleviate depressive symptoms or delay the progression of depression rather than cure it. Ginsenoside Rg1 is one of the main ginsenosides found in Panax ginseng roots. It improves depressive symptoms through various mechanisms, suggesting its potential as a treatment for depression. Materials and Methods We evaluated preclinical studies to comprehensively discuss the antidepressant mechanism of ginsenoside Rg1 and review its toxicity and medicinal value. Additionally, pharmacological network and molecular docking analyses were performed to further validate the antidepressant effects of ginsenoside Rg1. Results The antidepressant mechanism of ginsenoside Rg1 may involve various pharmacological mechanisms and pathways, such as inhibiting neuroinflammation and over‐activation of microglia, preserving nerve synapse structure, promoting neurogenesis, regulating monoamine neurotransmitter levels, inhibiting hyperfunction of the hypothalamic‐pituitary‐adrenal axis, and combatting antioxidative stress. Moreover, ginsenoside Rg1 preserves astrocyte gap junction function by regulating connexin43 protein biosynthesis and degradation, contributing to its antidepressant effect. Pharmacological network and molecular docking studies identified five targets (AKT1, STAT3, EGFR, PPARG, and HSP90AA1) as potential molecular regulatory sites of ginsenoside Rg1. Conclusions Ginsenoside Rg1 may exert its antidepressant effects via various pharmacological mechanisms. In addition, multicenter clinical case‐control and molecular targeted studies are required to confirm both the clinical efficacy of ginsenoside Rg1 and its potential direct targets.

Aims This study investigated the roles of lateral basal forebrain glial cell line–derived neurotrophic factor (GDNF) signaling and cholinergic neuron activity, apoptosis, and autophagy dysfunction in sleep deprivation–induced increased risk of chronic postsurgical pain (CPSP) in mice. Methods Sleep deprivation (6 h per day from −1 to 3 days postoperatively) was administered to mice receiving skin/muscle incision and retraction (SMIR) to determine whether perioperative sleep deprivation induces mechanical and thermal pain hypersensitivity, increases the risk of chronic pain, and causes changes of basal forebrain neurons activity (c‐Fos immunostaining), apoptosis (cleaved Caspase‐3 expression), autophagy (LC3 and p62 expression) and GDNF expression. Adeno‐associated virus (AAV)‐GDNF was microinjected into the basal forebrain to see whether increased GDNF expression could reverse sleep deprivation–induced changes in pain duration and cholinergic neuron apoptosis and autophagy. Cholinergic neurons were further depleted by mu p75‐SAP to examine whether the pain‐prolonging effects of sleep deprivation still exist. Results Perioperative sleep deprivation enhanced pain sensation and prolonged pain duration in SMIR mice, which was accompanied by decreased cholinergic neuron activity and GDNF expression, increased apoptosis, and autophagy dysfunction in the substantia innominata (SI), magnocellular preoptic nucleus (MCPO), and horizontal diagonal band Broca (HDB) (hereafter lateral basal forebrain). Normalizing cholinergic neuron GDNF expression by AAV‐GDNF in the lateral basal forebrain inhibited apoptosis and autophagy dysfunction and mitigated sleep deprivation–induced pain maintenance. Mice with selective lesion of lateral basal forebrain cholinergic neurons were resistant to the pain‐enhancing and prolonging effects of sleep deprivation and the pain‐alleviating effects of AAV‐GDNF therapy. Conclusions Perioperative sleep deprivation promotes chronicity of postsurgical pain possibly through decreasing basal forebrain GDNF signaling and causing cholinergic neuronal apoptosis and autophagy dysfunction.

Mitochondria, known as the “energy factory” of cells, are essential organelles with a double membrane structure and genetic material found in most eukaryotic cells. They play a crucial role in tumorigenesis and development, with alterations in mitochondrial structure and function in tumor cells leading to characteristics such as rapid proliferation, invasion, and drug resistance. Glioma, the most common brain tumor with a high recurrence rate and limited treatment options, has been linked to changes in mitochondrial structure and function. This review focuses on the bioenergetics, dynamics, metastasis, and autophagy of mitochondria in relation to glioma proliferation, as well as the potential use of mitochondria‐targeting drugs in glioma treatment.

Background Neurovascular coupling (NVC) reflects the close connection between neural activity and cerebral blood flow (CBF) responses, providing new insights to explore the neuropathological mechanisms of various diseases. Non‐dialysis patients with chronic kidney disease (CKD) exhibit cognitive decline, but the underlying pathological mechanisms are unclear. Methods The prospective study involved 53 patients with stage 1–3a CKD (CKD1–3a), 78 patients with stage 3b–5 CKD (CKD3b–5), and 52 healthy controls (HC). Our investigation involved voxel‐based assessments of both global and regional BOLD signal characteristics. Additionally, we explored the correlations between neuroimaging indices, Montreal Cognitive Assessment (MoCA) scores, and clinical laboratory findings. Results Compared to HC, the CKD3b–5 and CKD1–3a groups exhibited lower ALLF and ReHo in the default mode network (DMN), higher CBF in bilateral hippocampus (HIP), higher susceptibility values in bilateral caudate nucleus (CAU) and putamen (PUT), and lower susceptibility values in bilateral HIP. At the global level, the coupling coefficients were lower in CKD1–3a and CKD3b–5 groups than in HC. At the ROI level, the CBF‐ALFF and CBF‐ReHo coupling in HIP and basal ganglia regions were lower in CKD3b–5 groups than in the CKD1–3a group. Most importantly, susceptibility‐ALFF in ANG.R may mediate the effects of phosphorus on cognitive decompensation in patients with CKD1‐3a. Conclusions Non‐dialysis patients with CKD exhibit abnormal NCV, which is associated with the cognitive decline. Specifically, the susceptibility‐ALFF may serve as a valuable biomarker for early assessment of cognitive decline in CKD, offering insights into the pathogenesis of cognitive decline in CKD.

Background Major depressive disorder (MDD) is one of the most common mental disorders, and the number of individuals with MDD (MDDs) continues to increase. Therefore, there is an urgent need for an objective characterization and real‐time detection method for depression. Functional near‐infrared spectroscopy (fNIRS) is a non‐invasive tool, which is widely used in depression research. However, the process of how the brain activity of MDDs changes in response to external stimuli based on fNIRS signals is not yet clear. Method Energy landscape (EL) can describe the brain dynamics under task conditions by assigning energy values to each state. The higher the energy value, the lower the probability of the state occurring. This study compares the EL features of 60 MDDs with 60 healthy controls (HCs). Results Compared to HCs, MDDs have more local minima, smaller energy differences, smaller variations in basin sizes, and longer duration in the basin of global minimum (GM). The classification results indicate that using the four features above for depression detection yields an accuracy of 86.53%. Simultaneously, there are significant differences between the two groups in the duration of the major states. Conclusion The dynamic brain networks of MDDs exhibit more constraints and lower degrees of freedom, which might be associated with depressive symptoms such as negative emotional bias and rumination. In addition, we also demonstrate the strong depression detection capability of EL features, providing a possibility for their application in clinical diagnosis.

Aim Cerebral ischemic stroke (IS) is one of the leading causes of morbidity and mortality globally. However, the mechanisms underlying IS injury remain poorly understood. Ring finger protein 2 (RNF2), the member of the polycomb family (PcG), has been implicated in diverse biological and pathological conditions. However, whether RNF2 plays a role in IS progression is not clarified. This study aims to investigate the potential effects of RNF2 on IS. Methods The effects of RNF2 were studied in human postmortem IS brains, a rat model of IS, tunicamycin (TM)‐induced mouse neuroblastoma neuro2a (N2a) cells, and oxygen–glucose deprivation/reperfusion (OGD/R)‐induced SH‐SY5Y cells. Results Here, we demonstrated that RNF2 was markedly upregulated both in human postmortem IS brains and ischemic rat brains and RNF2 overexpression alleviated brain injury induced by middle cerebral artery occlusion by reducing neuron apoptosis. Mechanistically, we found that RNF2 is an E3 ubiquitin ligase for the mesencephalic astrocyte‐derived neurotrophic factor (MANF), which confers protection against brain ischemia. RNF2 interacted with MANF and promoted the monoubiquitination of MANF, consequently facilitating its stability and nuclear localization. Conclusion Collectively, RNF2 is identified as a critical inhibitor of IS injury by stabilizing MANF through monoubiquitination, suggesting that RNF2 is a potential therapeutic target for IS.

Background Dorsal raphe nucleus (DRN) serotonergic neurons projecting to the ventral tegmental area (VTA) neural circuit participate in regulating wake‐related behaviors; however, the effect and mechanism of which in regulating sleep–wake are poorly understood. Methods Fiber photometry was used to study DRN serotonergic afferent activity changes in the VTA during sleep–wake processes. Optogenetics and chemogenetics were took advantage to study the effects of DRN serotonergic afferents modulating VTA during sleep–wake. In vivo electrophysiology was employed to investigate how VTA neuronal firings were influenced by upregulation of DRN serotonergic afferents during sleep–wake. Results We found that DRN serotonergic afferent activity in the VTA was higher during wake than during NREM and REM sleep. Chemogenetic activation of VTA‐projecting DRN serotonergic neurons increased wake, and optogenetic activation of DRN serotonergic terminals in the VTA induced wake during NREM and REM sleep. Furthermore, we found that optogenetic activation of DRN serotonergic terminals in the VTA increased glutamatergic neuronal firing, decreased dopaminergic neuronal firing, but not influenced GABAergic neuronal firing during NREM sleep. Conclusion Our findings provide evidence in understanding the role of DRN serotonergic neurons‐VTA neural pathway in regulating sleep–wake, in which dynamic VTA dopaminergic, glutamatergic, and GABAergic neuronal firing changes responded to the wake promoting effect of DRN serotonergic afferents.

Introduction Neuromyelitis optica spectrum disorder (NMOSD) is a rare debilitating autoimmune disease of the central nervous system (CNS). This is the first‐in‐human dose‐escalation Phase I clinical study of BAT4406F, an antibody‐dependent cell‐mediated cytotoxicity (ADCC)‐enhanced fully humanized anti‐CD20 monoclonal antibody, in Chinese NMOSD patients. Patients and Methods Using a “3 + 3” design and based on the planned algorithm of dose escalation, the enrolled NMOSD patients were sequentially assigned to one of the five dose‐escalation cohorts of BAT4406F with a single intravenous dose, and were then followed for a 6‐month observation period. The maximum tolerated dose (MTD) and dose‐limiting toxicity (DLT), safety, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of BAT4406F were investigated, and the efficacy of BAT4406F in NMOSD was also preliminarily explored. Results Fifteen Chinese NMOSD patients were enrolled to receive BAT4406F of escalated doses ranging from 20 to 750 mg. No subjects experienced DLT at the studied doses. BAT4406F injection exhibited favorable safety, with most of the adverse events (AE) of CTCAE Grade 1 or 2 in severity, and no Grade ≥ 3 adverse drug reactions (ADR) or serious adverse reactions occurred in any subjects. With the dose increase of BAT4406F, the maximum plasma concentration (Cmax), area under concentration‐time curve from 0 to the last measurable timepoint (AUC0‐t) and area under concentration‐time curve from 0 to infinity (AUC0‐inf) showed an increasing trend, whereas the mean clearance (CLt), terminal elimination rate (λZ), and apparent volume of distribution (Vd) decreased. The mean elimination half‐life (T1/2) was ranged from 9.0–16.4 days. PK profile of BAT4406F was generally nonlinear. BAT4406F led to a rapid and significant B‐cell depletion in all dose groups. Single administration of 500 mg or 750 mg maintains the CD19⁺ B lymphocyte count below 10/μL within the whole 6‐month observation period. Three subjects were antidrug antibody (ADA) positive and all of them were neutralizing antibody (NAb)‐negative. On day 99/180 postdose, several groups had decreased expanded disability status scale (EDSS) scores compared to baseline. During the observation period, NMOSD relapse occurred in two patients (13.3%) and the other 13 (86.7%) subjects remained relapse free. Conclusion BAT4406F was well tolerated at doses up to 750 mg and showed an expected pharmacodynamic effect of significant and long‐term depletion of CD19⁺ B lymphocytes. It has also shown preliminary evidence of activity in NMOSD maintenance treatment, warranting further investigations. Trial Registration ClinicalTrials.gov identifier: NCT04146285

Aims Many factors affect the neuroinflammatory response in patients with Alzheimer disease (AD). Galectin‐3 (Gal‐3) is closely related to microglial activation in the nervous system and can promote the aggregation of cancer cells in tumors. This study aimed to investigate the mechanism by which farnesylthiosalicylic acid (FTS) affects neuroinflammation in Aβ1–42 mice through Gal‐3. Methods We used the Morris water maze, reverse transcription–polymerase chain reaction (RT–PCR), Western blotting, enzyme‐linked immunosorbent assay (ELISA), and immunofluorescence to conduct our study. Results FTS reduced the levels of proinflammatory factors and microglial activation in Aβ1–42 mice. FTS inhibited total and membrane expression levels of Gal‐3 in Aβ1–42 mice, and the anti‐inflammatory effect of FTS was reversed by Gal‐3–adeno‐associated viral (AAV). FTS reduced the expression levels of toll‐like receptors (TLRs), effects that were reversed by Gal‐3‐AAV. Moreover, FTS ameliorated Aβ oligomerization and accumulation in Aβ1–42 mice, effects that were also reversed by Gal‐3‐AAV. FTS, through the inhibition of the Gal‐3–c‐Jun N‐terminal kinase (JNK) pathway, reduced PS1 expression; in addition, inhibition of Gal‐3 increased the Aβ‐degrading enzymes in Aβ1–42 mice. FTS‐induced improvements in cognition in Aβ1–42 mice were reversed by Gal‐3‐AAV. Conclusion FTS may through inhibiting Gal‐3 reduce the expression of TLR4 and CD14 and alleviate Aβ pathology, downregulating Aβ‐stimulated TLR2, TLR4, and CD14 expression, and thus alleviate neuroinflammation in Aβ1–42 mice.

Background Focal to bilateral tonic–clonic seizures (FBTCS) represent the most severe seizure type in temporal lobe epilepsy (TLE), associated with extensive network abnormalities. Nevertheless, the genetic and cellular factors predispose specific TLE patients to FBTCS remain poorly understood. This study aimed to elucidate the relationship between brain morphometric alterations and transcriptional profiles in TLE patients with FBTCS (FBTCS+) compared to those without FBTCS (FBTCS−). Methods We enrolled 126 unilateral TLE patients (89 FBTCS+ and 37 FBTCS−) along with 60 age‐ and gender‐matched healthy controls (HC). We assessed gray matter volume to identify morphometric differences between patients and HC. Partial least squares regression was employed to investigate the association between the morphometric disparities and human brain transcriptomic data obtained from the Allen Human Brain Atlas. Results Compared with HC, FBTCS+ patients exhibited morphometric alterations in bilateral cortical and subcortical regions. Conversely, FBTCS− patients exhibited more localized alterations. Imaging transcriptomic analysis revealed both FBTCS− and FBTCS+ groups harbored genes that spatially correlated with morphometric alterations. Additionally, pathway enrichment analysis identified common pathways involved in neural development and synaptic function in both groups. The FBTCS− group displayed unique pathway enrichment in catabolic processes. Furthermore, mapping these genes to specific cell types indicated enrichment in excitatory and inhibitory neurons in the FBTCS− group, while FBTCS+ group only enriched in excitatory neurons. The distinct cellular expression differences between FBTCS− and FBTCS+ groups are consistent with the distribution patterns of GABAergic expression. Conclusion We applied imaging transcriptomic analysis linking the morphometric changes and neurobiology in TLE patients with and without FBTCS, including gene expression, biological pathways, cell types, and neurotransmitter receptors. Our findings revealed abnormalities in inhibitory neurons and altered distribution patterns of GABAergic receptors in FBTCS+, suggesting that an excitatory/inhibitory imbalance may contribute to the increased susceptibility of certain individuals to FBTCS.

Aims The study attempted to determine the underlying role and regulation mechanism of 3β‐hydroxysterol‐Δ24 reductase (DHCR24) in the pathophysiology of cerebral small vessel disease‐associated cognitive impairment (CSVD‐CI). An RNA high‐throughput sequencing and independent verification were conducted to identify potential circRNAs becoming the upstream regulator. Methods RNA sequencing was performed in whole‐blood samples in cohort 1 (10 CSVD‐CI and 8 CSVD with cognitively normal [CSVD‐CN] patients). The DHCR24 and candidate circRNAs were verified in an independent cohort 2 (45 CSVD‐CI participants and 37 CSVD‐CN ones). The study also analyzed comprehensive cognitive assessments, plasma molecular index, and brain structure imaging. Results The expression of DHCR24 and has_circ_0015335 in whole‐blood samples of CSVD‐CI patients was significantly reduced compared to CSVD‐CN patients in RNA sequencing and independent verification. Furthermore, the levels of DHCR24 and has_circ_0015335 were significantly related to global cognitive impairment in CSVD‐CI patients. Meanwhile, DHCR24 could regulate the correlation between has_circ_0015335 expression and alterations in brain cortex in surface area, thickness, and volume in CSVD‐CI patients. Additionally, hsa_circ_0015335 interacted with DHCR24 for plasma 24(S)‐hydroxycholesterol levels among CSVD‐CI patients. Conclusion Interaction between DHCR24 and hsa_circ_0015335 cognitively impaired CSVD by affecting brain cholesterol metabolism and brain structural changes.

Aims Existing observational studies examining the effect of body fat on the risk of Parkinson disease (PD) have yielded inconsistent results. We aimed to investigate this causal relationship at the genetic level. Methods We employed two‐sample Mendelian randomization (TSMR) to investigate the causal effects of body fat on PD, with multiple sex‐specific body fat measures being involved. We performed Bayesian colocalization analysis and cross‐trait meta‐analysis to reveal pleiotropic genomic loci shared between body mass index (BMI) and PD. Finally, we used the MAGMA tool to perform tissue enrichment analysis of the genome‐wide association study hits of BMI. Results TSMR analysis suggests that except waist circumference, higher measures of body fatness are associated with a decreased risk of PD, including BMI (OR: 0.83), body fat percentage (OR: 0.69), body fat mass (OR: 0.77), and hip circumference (OR: 0.83). The observed effects were slightly more pronounced in females than males. Colocalization analysis highlighted two colocalized regions (chromosome 3p25.3 and chromosome 17p12) shared by BMI and PD and pointed to some genes as possible players, including SRGAP3, MTMR14, and ADORA2B. Cross‐trait meta‐analysis successfully identified 10 novel genomic loci, involving genes of TOX3 and MAP4K4. Tissue enrichment analysis showed that BMI‐associated genetic variants were enriched in multiple brain tissues. Conclusions We found that nonabdominal body fatness exerts a robust protective effect against PD. Our colocalization analysis and cross‐trait meta‐analysis identified pleiotropic genetic variation shared between BMI and PD, providing new clues for understanding the association between body fat and PD.

Diagnosis and prediction of Alzheimer's disease (AD) are increasingly pressing in the early stage of the disease because the biomarker‐targeted therapies may be most effective. Diagnosis of AD largely depends on the clinical symptoms of AD. Currently, cerebrospinal fluid biomarkers and neuroimaging techniques are considered for clinical detection and diagnosis. However, these clinical diagnosis results could provide indications of the middle and/or late stages of AD rather than the early stage, and another limitation is the complexity attached to limited access, cost, and perceived invasiveness. Therefore, the prediction of AD still poses immense challenges, and the development of novel biomarkers is needed for early diagnosis and urgent intervention before the onset of obvious phenotypes of AD. Blood‐based biomarkers may enable earlier diagnose and aid detection and prognosis for AD because various substances in the blood are vulnerable to AD pathophysiology. The application of a systematic biological paradigm based on high‐throughput techniques has demonstrated accurate alterations of molecular levels during AD onset processes, such as protein levels and metabolite levels, which may facilitate the identification of AD at an early stage. Notably, proteomics and metabolomics have been used to identify candidate biomarkers in blood for AD diagnosis. This review summarizes data on potential blood‐based biomarkers identified by proteomics and metabolomics that are closest to clinical implementation and discusses the current challenges and the future work of blood‐based candidates to achieve the aim of early screening for AD. We also provide an overview of early diagnosis, drug target discovery and even promising therapeutic approaches for AD.

Objective Magnetic resonance‐guided laser interstitial thermal therapy (MRgLITT) is a novel tool and a minimally invasive treatment to drug‐resistant epilepsy (DRE). The focus of this research was to evaluate the effectiveness and safety of the newly developed dual‐wavelength dual‐output MRgLITT system LaserRO within two probe trajectories in treating DRE patients. Methods This is a retrospective analysis conducted at a single center, examining patients with DRE who received treatment with the LaserRO MRgLITT system. The system utilizes a sophisticated laser technology that can be configured as conventional single output for single wavelength or innovative dual outputs for dual wavelengths. The study involved a comprehensive review of patient information, encompassing demographics, seizure history, details related to the surgical parameters, and the subsequent clinical results. Primary outcome was post‐operation seizure outcome defined as Engel Scale Class at the end of follow‐up time. Results This study included a total of eight DRE patients received MRgLITT surgery between August 2022 and October 2023. Out of these, there were four mesial temporal lobe epilepsy (MTLE), three focal cortical dysplasia (FCD), and one cavernous malformation (CM) patients. Within the two probe trajectories, seven patients had single wavelength (980 or 1064 nm) laser treatment and one patient had dual‐wavelength (980 and 1064 nm) laser treatment. The median age of the patients was 27 (22–31) years, with a median follow‐up period of 9.7 (8.4–12.1) months. The mean BMI was recorded at 20.24 ± 2.95 kg/m², and epilepsy history was 13 ± 6 years. The median intraoperative blood loss was 5 (5–9) mL, operation time was 231 (169–254) minutes, and length of stay (LOS) was 3 (3–5) days. The mean ablation volume ratio was 96.52% ± 3.67%. In terms of outcomes, over a median follow‐up time of 9.7 (range 8.4–12.1) months, there were two patients got Engel I, five patients got seizure‐free, and one patient decreased 75% seizure. Importantly, no serious complications following the procedures occurred. Conclusions The preliminary results indicate that the MRgLITT procedure, which operates dual‐output laser with single or dual wavelengths (980/1064 nm) within the two trajectories, is both effective and safe as a minimally invasive approach for different types of DRE patients.