CNS Neuroscience & Therapeutics最新文献

Aims: Dl-3-n-butylphthalide (NBP) is a novel agent for acute ischemic stroke. This study aimed to investigate its effects on cortical angiogenesis and vasodilation during stroke recovery.

Methods: Mice underwent distal middle cerebral artery occlusion (dMCAO) and subsequently received NBP treatment. Therapeutic efficacy was measured by neurological deficits and infarct size. Angiogenesis was assessed by immunofluorescent staining. Laser speckle and two-photon microscopy imaging were employed to evaluate dynamic changes in cortical cerebral blood flow and vascular structure in vivo. The modulation of the Akt/GSK-3β signaling pathway was detected by western blotting.

Results: NBP administration promoted neurological recovery and reduced infarct size in the subacute phase. It facilitated cerebral blood flow and vasodilation, enhanced angiogenesis as evidenced by increased BrdU⁺/CD31⁺ cells and improved astrocyte/pericyte coverage around microvessels. Moreover, the pro-angiogenesis effect of NBP depends on the activation of the Akt/GSK-3β pathway, and this effect is blocked by LY294002.

Conclusion: In conclusion, NBP enhances recovery after ischemic stroke by promoting cortical angiogenesis and vasodilation through activation of the Akt/GSK-3β pathway. These findings highlight its therapeutic potential for delayed intervention in ischemic stroke.

Background: Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood.

Method: In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing.

Results: Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia-astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair.

Conclusions: Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation.

Introduction: Microglia, the resident immune cells of the central nervous system, rapidly activate after ischemic stroke and actively communicate with neurons, astrocytes, endothelial cells, and infiltrating peripheral immune cells. As ischemic stroke remains a major cause of death and long-term disability worldwide, growing evidence highlights that microglia-driven communication-through direct cell-cell contact, soluble factors, and extracellular vesicles-plays a central role in regulating neuroinflammation and shaping disease progression. A clearer understanding of these communication networks may help identify new therapeutic strategies targeting glial function.

Methods: This review summarizes recent advances in understanding microglial states after ischemic stroke and their communication with neural and peripheral immune cells. Literature was collected from PubMed and Web of Science, with attention to mechanisms involving direct cell-cell interaction, cytokine and chemokine signaling, extracellular vesicle communication, and newly described tunneling structures. Key regulatory processes at different pathological stages are compared.

Results: Experimental and clinical evidence shows that microglia display dynamic and heterogeneous activation patterns after ischemic stroke. Through diverse communication pathways, they influence neuronal survival, synaptic remodeling, inflammatory responses, and blood-brain barrier integrity. Soluble mediators-including cytokines, chemokines, and damage-associated molecular patterns-shape both local and systemic immune reactions, while extracellular vesicles regulate neuroinflammation and tissue repair by transferring bioactive molecules. Recently reported microglial tunneling structures further increase the complexity of intercellular communication. Together, these pathways determine the progression of ischemic injury and recovery.

Conclusions: Microglia act as central coordinators of communication among neurons, glial cells, and immune cells during ischemic stroke, thereby influencing disease severity and functional outcome. Clarifying microglia-mediated communication mechanisms may help guide the development of targeted immunomodulatory treatments. Continued research will be important for advancing these findings toward clinical translation.

Main problems: The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.

Methods: This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.

Results: Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood-brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.

Conclusions: Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.

Objective: Myocardial ischemia-reperfusion injury (MIRI) represents an inevitable risk event for acute myocardial infarction. We explored the mechanism of hypoxia-induced high-mobility group box 1 (HMGB1) promoting MIRI by modulating the NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis via the Nrf2/HO-1 pathway.

Methods: In vitro cultured mouse cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to establish an MIRI cell model, then treated with short hairpin-HMGB1, a NLRP3 agonist (Nigericin), and a Nrf2 inhibitor (ML385). Cell viability and injury were assessed via MTT and LDH assays. HMGB1 (nuclear/cytoplasm), Nrf2 (nuclear/cytoplasm), HO-1, NLRP3, ASC, cleaved Caspase-1, and GSDMD-N protein levels, and IL-1β and IL-18 levels in cell supernatants were determined by western blot and ELISA. HMGB1 and Nrf2 distribution were analyzed by immunofluorescence, with their interaction verified by co-immunoprecipitation. An MIRI mouse model was developed and treated with HMGB1 Box A for in vivo verification.

Results: H/R induction declined the nuclear HMGB1 protein level and cell viability, and intensified the cytoplasmic HMGB1 protein level, cell damage, and pyroptosis-related protein and inflammatory cytokine levels, which were averted by HMGB1 knockdown. NLRP3 activation partially reversed HMGB1 knockdown's effect on improving cardiomyocyte pyroptosis. Hypoxia-induced HMGB1 inhibited Nrf2/HO-1 activation by interacting with Nrf2. Nrf2/HO-1 suppression partly counteracted HMGB1 knockdown's suppressive effects on NLRP3 inflammasome activation and pyroptosis. HMGB1 suppressed the Nrf2/HO-1 axis to enhance NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis, thereby exacerbating MIRI in vivo.

Conclusion: Hypoxia induces HMGB1's nucleus-to-cytoplasm translocation, which binds to Nrf2 to repress Nrf2 nuclear translocation to suppress Nrf2/HO-1 activation to promote NLRP3 inflammasome/Caspase-1-mediated pyroptosis, thereby exacerbating MIRI.

Background: Post-stroke cognitive impairment (PSCI) is a prevalent and disabling condition with limited effective treatment options. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential non-invasive neuromodulation therapy. This review synthesizes recent advances in rTMS for PSCI, focusing on its mechanisms, therapeutic effects across cognitive domains, and safety profile.

Methods: We summarize evidence indicating that rTMS exerts its effects by modulating cortical excitability, promoting neuroplasticity via BDNF signaling, and regulating dysfunctional brain networks, particularly the central executive and default mode networks.

Results: Clinical studies demonstrate that high-frequency stimulation, primarily targeting the dorsolateral prefrontal cortex (DLPFC), can significantly improve memory, executive function, attention, and activities of daily living (ADLs) in patients with PSCI. A favorable safety profile is reported, with mild and transient adverse effects being most common. However, significant heterogeneity in stimulation parameters (e.g., frequency, intensity, pulses) exists across studies. Current evidence suggests that ensuring a sufficient number of stimulation pulses and duration may be necessary.

Conclusion: rTMS represents a promising therapeutic tool for PSCI, demonstrating benefits in key cognitive and functional domains. Future research must prioritize large-scale, standardized randomized controlled trials to optimize stimulation protocols, confirm long-term efficacy, and explore synergistic combinations with other rehabilitation strategies.

Background: Ischemic stroke remains a major cause of global disability and mortality, with blood-brain barrier (BBB) dysfunction being a pivotal event in its pathology. Major facilitator superfamily domain-containing 2a (Mfsd2a), a key lipid transporter at the BBB, has emerged as a promising yet underexplored therapeutic target.

Objective: This review proposes a unifying framework that positions Mfsd2a as a central indicator of ischemic stroke pathophysiology and a potential target for treatment. Although direct clinical evidence remains in its early stages, this review synthesizes foundational knowledge from diverse fields.

Methods: We revisit the established biological functions of Mfsd2a, including its role in inhibiting caveolae-mediated transcytosis and transporting omega-3 fatty acids, and detail its core mechanisms in maintaining BBB integrity. This review also correlates these functions with their significant downregulation following ischemic stroke. We then critically evaluate the limited but compelling preclinical evidence from models in which Mfsd2a has been directly targeted and explore innovative therapeutic strategies. Finally, we explicitly address the current limitations, including the scarcity of direct intervention studies, and outline a translational roadmap for future research.

Results: By integrating this dispersed evidence chain, this review aims to solidify the theoretical foundation for Mfsd2a-targeted therapies and accelerate their clinical development.

Conclusion: Targeting Mfsd2a shows a promising therapeutic strategy to protect the BBB and improve neurological outcomes after ischemic stroke.

Background: Systemic therapeutic options for meningiomas remain limited. Emerging evidence indicates meningiomas harbor an immunosuppressive microenvironment and programmed cell death ligand 1 (PD-L1) expression is significantly upregulated in both tumor cells and tumor-infiltrating immune cells. Here we conducted a single-arm, single-center, open-label, phase 2 clinical trial (NCT04728568) evaluating the programmed cell death receptor-1 (PD-1) inhibitor sintilimab in patients with recurrent/progressive meningiomas following standard surgery and/or radiotherapy.

Methods: Forty patients (9 grade 1, 18 grade 2, and 13 grade 3) received intravenous sintilimab (200 mg every 3 weeks). According to Response Assessment in Neuro-Oncology for meningioma (RANO-meningioma) criteria, the 6-month progression-free survival rate (PFS-6) was used as the primary endpoint. Secondary endpoints included the 12-month progression-free survival rate (PFS-12), PFS, overall survival (OS), and safety. Peripheral lymphocyte subpopulations, tumor-infiltrating lymphocyte (TIL) densities, and tumor mutational burden (TMB) were evaluated as immunocorrelated biomarkers.

Results: Patients with grade 1 exhibited a PFS-6 of 67.0%, a PFS-12 of 56.0%, and the median PFS was 14 months (95% CI: 0, 31.5). Grade 2/3 patients showed a PFS-6 of 42.0%, a PFS-12 of 19.0%, and the median PFS was 5.0 months (95% CI: 3.46, 6.54). The median OS was 27.0 months (95% CI: 17.26, 36.73) in grade 2/3 patients. The best outcome among all patients was stable disease (SD). Sintilimab was well tolerated without severe adverse events. A patient with a high TMB (13.14 muts/Mb) had a pseudoprogression with sintilimab and maintained stable disease among subsequent treatments. Among 3 patients with matched pre-/post-treatment tumor samples, 2 showed increased PD-1+ T cell expression after sintilimab.

Conclusion: Sintilimab failed to improve PFS-6 in both grade 1 and grade 2/3 recurrent/progressive meningiomas in this single-arm, single-center, and small-sample trial. When evaluating PD-1 inhibitor treatment for recurrent/progressive meningioma patients, who generally have a longer expected survival and high TMB, the use of the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria may be more appropriate to avoid overlooking potential clinical benefits.

Aims: To investigate the characteristics of hypoperfusion and structural impairment in patients with transient ischemic attack (TIA) or minor stroke (MS) with intracranial atherosclerotic stenosis (ICAS) and evaluate its impact on cognitive decline.

Methods: Cognitive function in 47 patients and 33 health controls (HC) was assessed using the Montreal Cognitive Assessment (MoCA) tool. Arterial spin labeling with two distinct postlabeling delays and 3D T1 imaging was conducted to assess cerebral blood flow (CBF), morphometric features, and asymmetry index (AI).

Results: Compared with HC, both the left and right involved patients showed reduced scores for total MoCA score. Comparisons of CBF with HC revealed that significant ischemic areas in patients were primarily localized to the perfusion territory of the middle cerebral artery in the affected hemisphere (p < 0.05, family-wise error [FWE] corrected). Despite morphometry abnormality being locally confined, AI exhibits more widespread alterations across a wider range of brain regions (both p < 0.05, FWE corrected). Both hypoperfusion and structural impairment were significantly associated with reduced MoCA score in left-involved patients, whereas only hypoperfusion showed a significant association in those with right-hemisphere involvement (p < 0.05, FWE corrected). Furthermore, the effect of ischemia on cognition was mediated by structural impairment and compensatory CBF simultaneously.

Conclusion: These findings highlight that hypoperfusion and structural impairment are already concerning and jointly associated with cognitive impairment in MS/TIA patients with ICAS, emphasizing the need for early detection and intervention.