Tonic activation of central nervous system (CNS) leptin receptors (LepRs) and melanocortin 4 receptors (MC4Rs) is critical for maintaining normal cardiometabolic function. Deficiency of CNS LepR or MC4R signaling causes severe obesity and is accompanied by multiple metabolic abnormalities including insulin resistance, glucose intolerance, and hyperlipidemia that are only partially explained by obesity. Defective LepR and MC4R signaling also causes dysfunction of the sympathetic nervous system (SNS) and blood pressure (BP) regulation. Hyperleptinemia and activation of the CNS melanocortin system in obesity are important compensatory mechanisms that attenuate abnormalities of glucose and lipid metabolism but may also contribute to SNS activation and increased BP. Despite potentially adverse effects of increases in SNS activity and BP, pharmacological activation of brain LepRs and MC4Rs may provide an important therapeutic approach for protecting target organs, such as the heart, kidneys, and brain, from ischemic injury by improving mitochondrial function and ATP production. However, additional preclinical studies are needed to address mechanistic questions before clinical studies are begun to test the effectiveness of leptin and MC4R agonists for treating people with ischemic injury of target organs.

Advances in neuropharmacology: Innovative drug strategies targeting synaptic plasticity, neuroinflammation, and ion channel regulation for future CNS treatments.

Novel Xanthene Derivatives for Neuroprotection in Alzheimer's Disease-Synthesis and Biological Assessment.

Neuromyelitis optica spectrum disorder (NMOSD) is a recurrent demyelinating disease of the central nervous system (CNS)characterized by inflammatory attacks on the CNS. This article reports a 56-year-old male patient admitted with over a year history of shortness of breath, a 2-week history of decreased vision in the right eye, and a 1-week history of hiccups. Physical examination revealed digital clubbing of both hands and bilateral lower lung Velcro rales. The patient had concurrent anti-aquaporin-4 (AQP4) antibody-positive NMOSD, primary Sjögren's syndrome (pSS), and interstitial lung disease (ILD), which were confirmed by characteristic clinical features, serological antibody testing, high-resolution chest CT, cranial and optic nerve MRI, and labial gland biopsy. Treatment included high-dose glucocorticoid pulse therapy combined with efgartigimod for pathogenic autoantibody clearance, inebilizumab targeted therapy, and mycophenolate mofetil (MMF) for long-term immunosuppression. After discharge, sequential maintenance therapy with oral prednisone and MMF tablets was administered. The patient's visual acuity and neurological symptoms improved. At follow-up >2 months after discharge, dyspnea recurred and worsened. After intensifying anti-infective therapy while maintaining the immunomodulatory regimen, the condition was effectively controlled, with follow-up high-resolution CT showing marked resolution of pulmonary interstitial exudates. This case suggests that anti-AQP4 antibodies may co-mediate pathological processes in both the central nervous system and peripheral organs. For patients with anti-AQP4 antibody-positive NMOSD, further screening for ILD or pSS is warranted. Early neurological assessment and antibody screening are crucial, facilitating early diagnosis and individualized treatment under multidisciplinary collaboration.

To investigate epigenetic and transcriptional alterations in children with Wiedemann-Steiner syndrome (WDSTS) due to variants of KMT2A gene using genome-wide DNA methylation array and RNA sequencing (RNA-seq), and identify the key pathways and candidate genes. A retrospective study was carried out for 16 children with WDSTS and 10 healthy controls who visited Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine between November 2016 and December 2024. Peripheral blood samples were collected. Genomic DNA and total RNA were extracted using commercially made kits. Genome-wide DNA methylation profiling was conducted to identify differentially methylated positions (DMPs) and annotated genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. RNA-seq was performed to identify differentially expressed genes (DEGs) and conduct GO/KEGG functional annotation. Methylation and expression data were integrated to identify overlapping genes showing significant changes at both levels, followed by GO, KEGG and gene-pathway network analyses. This study was approved by the Ethics Committee of the hospital (Ethics No.: GKLW-A-2024-006-01). A total of 2 652 DMPs corresponding to 1 262 genes were identified, which included 833 hypermethylated genes (66%) and 429 hypomethylated genes (34%). Hypermethylated genes were mainly enriched for functions related to cell junctions, while hypomethylated genes were significantly involved in nervous system development and morphogenesis. RNA-seq identified 2 627 DEGs, including 765 up-regulated genes (29%) and 1 862 down-regulated genes (71%). Up-regulated genes were mainly associated with immune-related processes, and down-regulated genes were mainly related to substance transport. Integrative analysis identified 93 overlapping genes with significant changes in both methylation and expression. And these genes were enriched in extracellular matrix-related processes, calcium ion binding, neurodevelopment, and cell adhesion. Key candidate genes, including LAMB1, LAMB2 and NID1, were further prioritized. Integrated analysis of DNA methylation and transcriptome data reveals WDSTS-related epigenetic-transcriptional alterations and provides clues for exploring disease mechanisms and optimizing diagnostic strategies.

Precision nose-to-brain therapeutics: Advances in drug delivery systems and emerging preclinical models.

Effective ropivacaine delivery using lipid nanoparticles enables simultaneous cancer therapy and pain control.

The hallmark of secondary spinal cord injury (SCI) is destruction of the blood-spinal cord barrier (BSCB). Nuclear heme oxygenase-1 (NHO-1) is involved in neuroprotection in the central nervous system. Previously, we demonstrated that adenoviral delivery of nuclear-targeted HO-1 (NHO-1) alleviates BSCB disruption, but the molecular mechanisms remain to be clarified. This study was conducted to investigate the specific regulatory mechanisms regulating tight junctions in the BSCB. A moderate T10 contusion SCI was induced in adult male Sprague-Dawley rats. Nuclear-targeted HO-1 was delivered by adenoviral pretreatment 7 days before injury. Spinal cords were collected at 24 h post-SCI for RNA-seq and quantitative real-time-PCR validation. BSCB permeability (Evans Blue), tight junction phosphorylation (western blot), and locomotor function (Basso, Beattie, and Bresnahan score and footprint analysis) were assessed, with intrathecal corticotropin-releasing hormone (CRH)-R1 agonist (Cortagine) or antagonist (Antalarmin) administered after SCI. RNA-seq identified 10 overlapping differentially expressed genes across pairwise comparisons; subsequent Venn-based prioritization and quantitative real-time-PCR validation identified Crh as the most consistently regulated candidate. Functional assays demonstrated that nuclear HO-1, particularly when combined with CRH receptor activation, decreased leakage of BSCB via enhancing phosphorylation of tight junction protein which disappears after application of CRH inhibitor. These results indicate that nuclear-targeted HO-1 promotes BSCB repair after SCI by transcriptionally upregulating Crh and enhancing CRH-dependent phosphorylation of tight junction proteins (Claudin-5 and Occludin).

Central nervous system astrocytes have an intricate, highly branched morphology. Proper development of perisynaptic astrocyte processes is necessary for tripartite synapse formation and function. However, cellular pathways orchestrating this development are largely unknown. Neuroligins (NLs) 1-3 regulate astrocyte morphogenesis via transcellular adhesions with neuronal neurexins. Here, we found an astrocytic NL2-based mechanism governing morphogenesis. Through structure and function studies, we identified a WW-binding motif within the NL2 intracellular domain required for astrocyte morphogenesis. Using cell-specific in vivo proximity labeling (iBioID), we found that each NL displays distinct protein-protein interactions within astrocytes, distinct from the neuronal NL2-binding partners. From these data, we identified a role for WW domain-containing E3 ubiquitin ligase Nedd4l in astrocyte morphogenesis. Biochemical assays revealed Nedd4l ubiquitinates and stabilizes NL2, and this ubiquitination is required for astrocyte morphogenesis. This study shows that NLs have nonoverlapping roles in controlling astrocyte growth and uncovers a molecular mechanism of how NL2 mediates astrocyte morphogenesis.

The complex structure of astrocytes allows for nervous system function; however, mechanisms underlying astrocyte morphogenesis remain unclear. Sakers et al. (https://doi.org/10.1083/jcb.202512111) find that astrocyte neuroligins (NLs) are functionally diverse, and intracellular ubiquitination of astrocyte NL2 by Nedd4l promotes astrocyte morphogenesis.

Pain is a multidimensional experience emerging from the coordinated activity of distributed neural circuits that integrate sensory, emotional, and cognitive information. The purpose of this review is to highlight and synthesise current understanding of the circuit mechanisms underlying ascending nociception and descending modulation of pain, with particular emphasis on brainstem areas and their involvement in shaping pain perception. We discuss how dysregulation of these control systems may contribute to persistent pain states. It is consistently demonstrated that pain is both a dynamic and context-dependent process, shaped by extensive bidirectional interactions within the central nervous system. In humans, nociceptive signals transmitted through spinal and trigeminal pathways engage brainstem and forebrain networks that generate protective behaviours and aversive subjective states, while descending modulatory systems exert powerful control over signal gain at early relay sites. Recent evidence asserts that this reciprocal organisation is what allows pain to be flexibly adjusted according to internal state, environmental threat, learning history, and behavioural priorities. Understanding the coordinated neural and behavioural responses that lead to typical pain processing, and which components of these myriad systems become maladaptive in clinical pain settings, is critical for optimising treatment selection to individual symptom profiles.

The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.

Neuro-tumor-immune crosstalk in pancreatic cancer: Mechanisms and therapeutic insights.

Brain-organ axis: How does stress regulate peripheral immunity through neural signaling?

Evolution of neuropeptides: From diffusing molecules to modulators of synaptic transmission.

Varicella-zoster virus (VZV), a neurotropic α-herpesvirus, establishes lifelong latency in the nervous system after primary infection. Reactivation leads to herpes zoster (HZ), which can result in severe neurologic complications including postherpetic neuralgia, vasculopathy, encephalitis, meningitis, myelopathy, cranial neuropathy, and optic neuritis. These complications may occur even in the absence of a characteristic rash, making early recognition crucial for timely antiviral therapy to maximize the likelihood of a good outcome. Clinical manifestations of VZV-associated neurologic disorders vary and often mimic other infectious and inflammatory conditions, further complicating timely diagnosis. Among available diagnostic imaging modalities, MRI is the most useful modality for diagnosis of VZV-related neurologic disorders. Recent high-resolution MRI techniques, such as three-dimensional fluid-attenuated inversion recovery and MR neurography, increase the sensitivity for detecting subtle signal intensity abnormalities, and vessel wall imaging is capable of noninvasively demonstrating vascular involvement. Accurate diagnosis requires the integration of imaging findings, clinical assessment, and cerebrospinal fluid (CSF) analysis. In particular, the detection of VZV DNA with a polymerase chain reaction test and testing for anti-VZV immunoglobulin G antibodies in CSF are essential. Given the myriad clinical manifestations of HZ, radiologists may be the first to recognize nervous system pathologic conditions that are related to VZV, which is particularly important because the incidence increases in the aging population. The authors provide a comprehensive update on the epidemiologic, pathophysiologic, and imaging features of VZV-related neurologic disorders. Increased awareness and accurate imaging interpretation can expedite diagnosis and facilitate appropriate clinical management of these patients to improve outcomes. ©RSNA, 2026.

Takostubo syndrome: A mind-body response to stress.

Da-Bu-Yin-Wan and Qian-Zheng-San regulate neuroinflammation and intestinal permeability through the microbiota-gut-brain axis in Parkinson's disease mice.

FDA-approved RET protein-tyrosine kinase inhibitors in the management of RET-driven thyroid and lung cancer.

Ranolazine, approved for the symptomatic treatment of chronic stable angina, is currently indicated as an additional treatment when angina symptoms are not controlled with traditional drugs such as beta-blockers and calcium channel blockers. This review summarizes clinical studies that support current established recommendations for its use and discusses emerging evidence in clinical settings other than ischemic heart disease. A growing number of studies have shown a significant antiarrhythmic effect of this molecule, at both atrial and ventricular levels. Treatment with ranolazine has been associated with a reduced risk of atrial fibrillation and a greater likelihood of restoring sinus rhythm. Additionally, ranolazine is associated with a reduced risk of ventricular arrhythmias in various clinical settings. Ranolazine also plays a modest but clinically significant role in controlling glucose metabolism and is mentioned in the 2023 European Society of Cardiology guidelines on diabetes as a treatment capable of reducing glycated hemoglobin, especially in diabetic patients with poor metabolic control. In cardio-oncology, preclinical and clinical studies have shown a potential cardioprotective effect of ranolazine during certain chemotherapy treatments. In vitro and in vivo studies also suggest a favorable impact of ranolazine on the nervous system, with potential therapeutic effects, for example, in the treatment of neuropathic pain. Although the aforementioned contexts require further evaluation in targeted clinical trials, in all these areas ranolazine's pharmacodynamic profile suggests clinical benefits. Overall, a review that integrates current recommendations with a critical analysis of emerging therapeutic frontiers lays the foundation for an increasingly personalized therapeutic approach.