Abstract Intracerebral hemorrhage (ICH) under chronic high‐altitude exposure exhibits distinct epidemiological characteristics: higher incidence, younger age at onset, more severe perihematomal edema, and worse clinical outcomes. However, the specific mechanisms underlying its pathogenesis and progression remain incompletely understood. In this review, we demonstrate that immigrant populations subjected to chronic high‐altitude exposure are at increased risk of ICH relative to indigenous populations (Tibetans, Andeans), primarily due to the lack of adaptive genetic variations such as endothelial PAS domain protein 1 and small ubiquitin‐like modifier‐specific peptidase 1. Additionally, high‐altitude polycythemia, high‐altitude hypertension, and hyperuricemia have been identified as critical risk factors for high‐altitude ICH. Further mechanistic exploration reveals that chronic high‐altitude exposure‐induced brain injury is structurally underpinned by vascular‐immune‐neuronal network dysfunction, which entails the interactive crosstalk of “vascular injury‐immune infiltration‐neurodegeneration” and thereby creates a unique pathological niche for high‐altitude ICH. At the molecular level, the core driving mechanism is the reciprocal activation of the hypoxia‐inducible factor pathway, oxidative stress, and neuroinflammation. This review represents a comprehensive synthesis of chronic high‐altitude exposure‐related brain injury and the subsequent exacerbation of ICH, providing a valuable reference for future research on high‐altitude encephalopathy.
Abstract Background Efgartigimod disrupts the recycling of pathogenic IgG autoantibodies and may represent a candidate therapy for autoimmune encephalitis. This real‐world study evaluated the clinical efficacy, safety, and impact of efgartigimod on brain inflammation. Methods This multicenter, single‐arm, prospective, observational real‐world study enrolled 18 patients, including 10 with anti‐N‐methyl‐ d ‐aspartate receptor (NMDAR) encephalitis and 8 with anti‐leucine‐rich glioma‐inactivated 1 (LGI1) encephalitis. Participants received intravenous efgartigimod at a dose of 10 mg/kg weekly for a total of two to four doses, with or without concomitant immunosuppressive therapy. Anti‐NMDAR‐IgG/LGI1‐IgG antibody titers, modified Rankin scale (mRS), Clinical Assessment Scale in Autoimmune Encephalitis (CASE), Montreal Cognitive Assessment, Mini‐Mental State Examination, and Glasgow Coma Scale scores were assessed at baseline and at 1, 2, 3, 8, and 12 weeks after treatment. 18 F‐DPA714 positron emission tomography/magnetic resonance imaging was used to monitor brain inflammation in a subset of patients. Analyses were performed using SPSS 26.0 and Prism 10.0. Non‐parametric tests, including Wilcoxon signed‐rank, Mann–Whitney U , and Friedman tests with Bonferroni post hoc correction, were applied. Two‐tailed p < 0.05 indicated statistical significance; corrected p < 0.01 was applied for five longitudinal pairwise comparisons. Results At the final follow‐up, median mRS scores in patients with anti‐NMDAR encephalitis decreased significantly from 3 (range, 1–5) before treatment to 1 (range, 0–3) after treatment ( Z = −2.588, p = 0.007). Median CASE scores decreased from 7.5 (range, 1–27) to 1.5 (range, 1–7) post‐treatment ( Z = −2.714, p = 0.005). In patients with anti‐LGI1 encephalitis, CASE scores decreased markedly from 3 (range, 1–7) to 1.5 (range, 0–2) at the last visit ( Z = −2.154, p = 0.046). All 18 patients underwent baseline imaging, and 7 patients underwent follow‐up PET/MRI examinations. A subset of patients ( n = 4; three with anti‐NMDAR encephalitis and one with anti‐LGI1 encephalitis) showed reduced uptake in specific brain regions accompanied by symptom improvement. Both initial and follow‐up imaging results were negative for the remaining three patients. Comparative analysis of efgartigimod monotherapy versus combination therapy with glucocorticoids and immunosuppressants revealed no significant differences in key outcomes, indicating that the therapeutic effect was independent of concomitant medication use. Efgartigimod was well tolerated. One patient (1/18) developed mild pneumonia, but no other serious adverse events were reported. Conclusion Efgartigimod may represent a novel therapeutic option for anti‐NMDAR and anti‐LGI1 encephalitis, potentially improving clinical outcomes in affected patients. Registration Info This study was registered at the National Clinical Research Center ( https://www.medicalresearch.org.cn ; No. MR‐31‐24‐053225).
Abstract Antimicrobial agents, originally developed for infectious diseases, have become attractive candidates for repurposing in neurodegenerative and neuroinflammatory diseases owing to their anti‐inflammatory, antioxidant, immunomodulatory, and neuroprotective activities. In this review, we critically examine the therapeutic potential of selected antimicrobial classes, including tetracyclines (e.g., minocycline), macrolides (e.g., azithromycin), antimalarial agents (e.g., chloroquine/hydroxychloroquine), sulfones (e.g., dapsone), and antiparasitic agents (e.g., ivermectin), in non‐infectious neurological diseases. We performed a narrative review of pre‐clinical and clinical studies to investigate the effects of these agents on the main neuropathological mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, impaired autophagy, and gut–brain axis dysregulation. The available evidence suggests that many of the antimicrobial agents have beneficial effects in a number of neurological disorders, including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, and traumatic brain injury. These agents have been shown to modulate microglia activation, to inhibit production of pro‐inflammatory cytokines, and to alter intracellular signaling pathways, including nuclear factor kappa‐light‐chain‐enhancer of activated B cells. Furthermore, by reshaping the gut microbiota, antimicrobials modulate immune signaling, alter neurotransmitter levels, and compromise blood–brain barrier integrity—thereby positioning the gut–brain axis as central to their mechanism of action. Repurposing antimicrobial agents is a pragmatic and novel approach to treat complex neurological disorders with available approved drugs. Despite the encouraging evidence, we must carefully manage challenges such as antimicrobial resistance, off‐target effects, and regulatory considerations. Further well‐designed clinical trials are essential to validate their long‐term safety and efficacy in neurodegenerative and neuroinflammatory diseases.
Background:Traumatic brain injury (TBI) causes long-term disability, with inflammation contributing to both primary and secondary brain damage. Extracellular adenosine triphosphate (ATP) and its receptor purinergic receptor X7 (P2X7) drive neuroinflammation and represent promising therapeutic targets. Therefore, we developed a strategy to mitigate acute post-TBI inflammation using mesenchymal stem cells (MSCs) engineered to deliver a P2X7-blocking nanobody (P2X7nb). Methods:Primary MSCs were transfected in vitro with bicistronic messenger RNA (mRNA) encoding P2X7nb and a haloalkane dehalogenase Tag reporter, with nanobody secretion confirmed by enzyme-linked immunosorbent assay (ELISA). In vivo, TBI was induced in mice using the closed-head injury model. Twenty-4 hours post-TBI, MSCs labeled with iron oxide nanoparticles were administered via intra-arterial injection into the internal carotid artery. Dynamic 9.4 T magnetic resonance imaging (MRI) using susceptibility-weighted imaging (SWI) allowed real-time monitoring of cellular accumulation. Behavioral performance was assessed using the beam walk test, while mice were euthanized on Day 4 post-TBI for immunofluorescence analysis of cell localization. Data were analyzed using either an unpaired t-test or Mann-Whitney U test, depending on data distribution, with statistical significance set at p < 0.05. Results:Transfection (38.9% efficiency) and release of P2X7nb were confirmed, with a peak secretion of 17.29 ± 1.84 ng/mL. SWI MRI revealed accumulation of labeled MSCs in the brain post-injection, with a persistent hypointense signal ranging from 2.45% ± 2.93% to 0.77% ± 0.88% of cell area (% of right hemisphere) over 3 days. Behavioral assessment using the beam walk test revealed no cell transplantation-related motor impairment, while histology confirmed the presence of transfected MSCs in injured brain tissue. Conclusion:MSCs expressing a P2X7nb are detectable in the injured brain following intra-arterial delivery for at least 3 days, without producing adverse effects. These findings provide insights into cell-based immunomodulatory therapies targeting neuroinflammation in TBI and highlight the utility of noninvasive MRI to monitor therapeutic cell biodistribution and persistence.
