Chronic unpredictable mild stress (CUMS) induces depression-like behaviors and may exacerbate pain perception through neuroinflammatory mechanisms, in which microglial polarization plays a crucial role. However, its effects on fascial tissues remain unclear. This study aimed to investigate the regulatory effects of transcranial direct current stimulation (tDCS) on neuroinflammation and structural/functional alterations of lumbar fascia in CUMS-induced rats, with particular focus on microglial involvement. An 8-week CUMS depression model was established in Sprague-Dawley (SD) rats, followed by tDCS intervention. Comprehensive assessments were performed using behavioral tests, ultrasonography, hematoxylin-eosin (H&E) staining, Masson staining, immunohistochemistry (IHC), and Western blot (WB) to evaluate depression-like behaviors, neuronal damage, fascial morphology, and inflammatory protein expression. Results demonstrated that CUMS rats exhibited significant depression-like behaviors, neuronal injury, and neuroinflammatory responses, accompanied by fibrosis, thickening, and inflammatory infiltration in the lumbar fascia. Immunological analysis revealed enhanced M1 microglial activation with concurrent suppression of M2 polarization in the CUMS group. Following tDCS intervention, rats showed marked improvements in depression-like behaviors, reduced neuronal damage, attenuated fascial fibrosis and inflammation, as well as decreased fascial thickening and edema on ultrasonography. The enhanced hindlimb weight-bearing capacity suggested alleviation of low back pain. Mechanistic studies indicated that tDCS effectively suppressed M1 microglial activation while promoting M2 polarization. These findings suggest that the therapeutic effects of tDCS on CUMS-induced depressive-like behaviors may involve modulation of microglial polarization and attenuation of neuroinflammatory and fascial inflammatory responses.

Parkinson's disease (PD) is a progressive neurodegenerative disease that is associated with the loss of dopaminergic neurons and the formation of α-synuclein aggregates in the brain. Changes in the gut microbiota have been closely associated with PD pathophysiology and may contribute to disease-related processes through neuroinflammatory, metabolic, and immune-mediated mechanisms. This review explores the connection between the microbiome-gut-brain axis and Parkinson's disease and highlights new microbiome-based therapeutic interventions to help manage the disease. The extensive literature review was conducted using peer-reviewed articles from scientific databases such as Google Scholar, PubMed, and Scopus, and included articles concerned with opposing gut microbiota changes, mechanistic pathways, and microbiome-based targeted therapeutic strategies for PD. Existing data suggest that gut dysbiosis may contribute to mechanisms associated with PD pathogenesis through alterations in immune responses, α-synuclein aggregation, and neurotransmitter signalling. Restoration of microbial balance and alleviation of neurological and gastrointestinal symptoms are potential benefits of therapeutic interventions targeting microorganisms, including probiotics, prebiotics, dietary changes, and faecal microbiota transplantation (FMT). The microbiome-gut-brain axis is a promising approach to preventing and treating Parkinson's disease, but additional clinical trials are needed to determine its long-term effectiveness and safety.

Traumatic brain injury (TBI) is commonly accompanied by aberrant microglial activation, uncontrolled neuroinflammation and subsequent neurological dysfunction. Ginkgolide B (GB) exerts prominent neuroprotective and anti-inflammatory activities; however, the precise molecular mechanism underlying its therapeutic efficacy against TBI remains poorly defined. The present study aimed to explore whether GB relieves TBI by modulating the HIF-1α/AKT/mTOR cascade and redirecting microglial polarization. A controlled cortical impact (CCI) model was established in mice followed by intraperitoneal GB administration. Network pharmacology, molecular docking and GEO database mining were performed to screen core therapeutic targets. An in vitro inflammatory model was constructed using LPS-stimulated BV2 microglia, CETSA and DARTS assays provided supportive evidence for a potential physical association between GB and HIF 1α, with subsequent rescue experiments implemented for mechanistic verification. In vivo behavioral assessments revealed that GB significantly mitigated acute neurological deficits, improved subacute motor coordination, and rescued chronic cognitive impairment and anxiety-like behaviors in TBI mice. Mechanistically, GB suppresses the HIF 1α/AKT/mTOR signaling cascade in a HIF 1α dependent manner. M1-type microglial polarization, reduced pro-inflammatory cytokine secretion and elevated the levels of anti-inflammatory cytokines. Notably, HIF-1α overexpression abolished the neuroprotective effects of GB, whereas HIF-1α knockdown recapitulated GB-mediated beneficial phenotypes. Collectively, GB acts through the candidate functional target HIF 1α to block the HIF 1α/AKT/mTOR pathway, ameliorates neuroinflammation through regulating microglial phenotypic transition, and ultimately alleviates neurological damage post-TBI. This work provides experimental evidence for the preclinical application of GB in TBI intervention.

Immune checkpoint inhibitors (ICIs) have significantly improved survival in patients with advanced lung cancer. However, they can induce immune-related adverse events (irAEs), including neurological complications such as protein-like 2 (CASPR2) antibody-associated neurological syndromes. This form of autoimmune neuroimmunological disease is associated with antibodies against contactin-associated CASPR2 and typically presents as limbic encephalitis, Morvan's syndrome, or peripheral nerve hyperexcitability. Clinical phenotypes often include cognitive impairment, memory deficits, dysautonomia, and may include cerebellar ataxia as an expanded phenotypic feature. While CASPR2 antibody-associated neurological syndromes presents with typical clinical features, it lacks a single specific manifestation. Furthermore, reported cases secondary to ICI therapy are extremely rare, and its symptoms overlap with those of lung cancer brain metastasis-collectively rendering diagnosis challenging. We report the case of a 46-year-old woman with advanced non-small cell lung cancer (NSCLC) who developed cerebellar syndrome accompanied by cognitive and autonomic symptoms manifesting after one week after the 2nd cycle of tislelizumab (the 4th total cycle of PD-1 inhibitor therapy). Serum testing revealed CASPR2 antibodies at a titer of 1:30 (cell-based assay), while cerebrospinal fluid (CSF) CASPR2 antibodies were negative and brain MRI showed no typical inflammatory changes. The patient's neurological symptoms resolved completely within 1 week after high-dose methylprednisolone and intravenous immunoglobulin treatment, But immune checkpoint inhibitor (ICI) therapy was permanently discontinued, and the patient subsequently died at home. The exact cause of death remains unclear, though it is presumed to be related to disease progression. A systematic literature review conducted upon submission identified only one previously reported peer-reviewed case of ICI-induced CASPR2 encephalitis, which also responded to corticosteroids. To our knowledge, this report describes the second documented case globally and the first associated with tislelizumab exposure. This case underscores that anti-PD-1 therapy can trigger this rare yet serious autoimmune neurological subtype.

Glioblastoma (GB), defined here primarily as adult-type Isocitrate dehydrogenase-wildtype high-grade glioma, according to the 2021 World Health Organization classification, is an aggressive primary brain tumor characterized by local and systemic immunosuppression, therapeutic resistance, and poor clinical outcomes. Although considerable attention has focused on adaptive immune responses in GB, innate immune cells centrally regulate the tumor microenvironment. They may influence tumor progression, immune evasion, and treatment response. The strength of evidence varies substantially across innate immune populations, ranging from well-characterized myeloid compartments, such as tumor-associated macrophages, dendritic cells, myeloid-derived suppressor cells, and neutrophils, to less explored granulocytic and lymphoid subsets, including natural killer cells, innate lymphoid cells, eosinophils, mast cells, and basophils. In this review, we discuss the context-dependent roles of these cells in tumor surveillance and promotion, their interactions with GB stem-like cells, their contributions to immunosuppression and therapeutic resistance, and their potential relevance as prognostic biomarkers or therapeutic targets. By integrating clinical observations with experimental evidence, we highlight current strategies to reprogram innate immunity in GB and identify key limitations that must be addressed before innate immune-based approaches can be translated more effectively into clinical practice.

Microglia are the resident immune cells of the brain and serve as key regulators of innate immune responses within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiprotein complex that plays a central role in innate immunity, and its excessive activation contributes to the pathogenesis of neurodegenerative diseases. Nilotinib, a second-generation tyrosine kinase inhibitor, has recently attracted attention due to its neuroprotective and immunomodulatory properties in the CNS. In the present study, we investigated the effects of nilotinib on NLRP3 inflammasome activation, GSDMD/NINJ1-mediated pyroptosis, NF-κB signaling, BAG3-dependent aggrephagy, and ESCRT-III-mediated plasma membrane repair in LPS plus ATP-induced murine N9 microglial cells. Our findings demonstrated that nilotinib significantly attenuated NLRP3 inflammasome activation, as evidenced by reduced NLRP3 expression, decreased caspase-1 activation, and suppressed secretion of proinflammatory cytokines IL-1β and IL-18 through modulation of the IκBα/NF-κB signaling axis. Furthermore, nilotinib markedly inhibited pyroptotic cell death by reducing GSDMD-N and NINJ1 expression, thereby preserving membrane integrity. In parallel, nilotinib enhanced BAG3-dependent selective autophagy and increased LC3B expression, suggesting activation of aggrephagy pathways involved in the clearance of inflammasome-associated components. Notably, nilotinib also restored VPS4A expression, indicating activation of ESCRT-III-mediated plasma membrane repair mechanisms. Collectively, our results reveal that nilotinib exerts a multi-layered regulatory effect on microglial inflammatory responses by suppressing inflammasome activation and pyroptosis while promoting autophagy-dependent clearance and membrane repair pathways. These findings highlight a novel integrative mechanism linking autophagy, pyroptosis, and membrane repair in the neuroprotective actions of nilotinib.

Purinergic 2X7 receptor (P2X7R) is considered to play a critical role in neurological diseases, including epilepsy, and has also been proposed as a potential marker for neuroinflammation. This study aimed to validate the binding properties of the novel P2X7R radiotracer, [[3]H]JNJ-64413739, in rat brain using in vitro autoradiography, and additionally to explore spatial and temporal changes in P2X7R binding levels in a rat model of temporal lobe epilepsy using intrahippocampal administration of kainic acid (KA). Saturation of [[3]H]JNJ-64413739 to brain sections yielded a KD of approximately 3 nM, with full saturation around 10 nM. The radiotracer was displaced with a structurally different P2X7R ligand, JNJ-47965567, indicating high affinity and specificity to rat P2X7R. A bilateral increase in [[3]H]JNJ-64413739 binding was observed in the hippocampal formation few days after status epilepticus, peaking at day 30, and remained stable at this high level until day 90. Similar temporal profiles were identified in subcortical regions such as the thalamus. Interestingly, no change in binding was observed in the temporal and piriform cortices until day 30 where a dramatic increase occurred. Also, in the corpus callosum, significant increase was detected 30 days after the seizure. These results show that [[3]H]JNJ-64413739 binding to P2X7R, likely reflecting inflammation, is increased at delayed time points and exhibit region-specific patterns that is different from acute effects. Our findings suggest that P2X7R may contribute to sustained neuroinflammation and may be involved in those changes leading to epileptogenesis and the development of chronic epilepsy.