Previous studies showed that TNF-α could activate voltage-gated Na+ channels (VGSCs) in the peripheral nervous system (PNS). Since TNF-α is implicated in many central nervous system (CNS) diseases, we examined potential effects of TNF-α on VGSCs in the CNS. Effects of TNF-α (1–1000 pg/mL, for 4–48 h) on VGSC currents were examined using whole-cell voltage clamp and current clamp techniques in primary culture of mouse cortical neurons. Expression of Nav1.1, Nav1.2, Nav1.3, and Nav1.6 were examined at both the mRNA and protein levels, prior to and after TNF-α exposure. TNF-α increased Na+ currents by accelerating the activation of VGSCs. The threshold for action potential (AP) was decreased and firing rate were increased. VGSCs were up-regulated at both the mRNA and protein levels. The observed effects of TNF-α on Na+ currents were inhibited by pre-incubation with the NF-κB inhibitor BAY 11–7082 (1 μM) or the p38 mitogen-activated protein kinases (MAPK) inhibitor SB203580 (1 μM). TNF-α increases Na+ currents by accelerating the channel activation as well as increasing the expression of VGSCs in a mechanism dependent upon NF-κB and p38 MAPK signal pathways in CNS neurons.

Traumatic brain injury (TBI) triggers both immediate (primary) and long-term (secondary) tissue damages. Secondary damages can last from hours to days or even a lifetime. Secondary damages implicate several mechanisms, including influence of inflammatory mediators, mainly cytokines, on excitability of ion channels. However, studies should further explore the effects of inflammatory cytokines on voltage-gated sodium channels (VGSCs) and excitability in distal intact neurons. Mixed cultures of mouse cortical astrocytes and neurons were subjected to mechanical injury (trauma) to mimic TBI in vitro. Expression of various cytokines in these cultures were measured by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. A trauma-conditioned medium with or without brain-derived neurotrophic factor (BDNF) was added to mouse primary cortical neurons for 6 and 24 h to mimic combined effects of multiple inflammatory cytokines on VGSCs. Spike behaviors of distal intact neurons were examined by whole-cell patch-clamp recordings. Mechanical injury in mixed cortical neuron–astrocyte cultures significantly increased expression levels of multiple cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-C motif) ligand-5, IL-10, and transforming growth factor-β1, at 6 and 24 h after injury. Incubation in trauma-conditioned medium increased functional VGSCs in neuronal membranes and Na+ currents. Enhanced VGSCs were almost completely abolished by BDNF, and reinforcement of Na+ currents was also reduced in a dose-dependent manner. BDNF (30 ng/mL) also significantly reversed reduced neuronal cell viability, which was induced by medium conditioned at 6 h. At 6 and 24 h, trauma-conditioned medium significantly increased spike frequency but not spike threshold. In TBI, the combined effect of inflammatory cytokines is directly involved in VGSC, Na+ current, and excitability dysfunction in distal intact neurons. BDNF may partly exert neuroprotective effects by maintaining balance of VGSC function in distal intact neurons.

Purpose. To explore the potential of monocyte-to-lymphocyte ratio (MLR) at hospital admission for predicting acute traumatic intraparenchymal hematoma (tICH) expansion in patients with cerebral contusion. Patients and Methods. This multicenter, observational study included patients with available at-hospital admission (baseline) and follow-up computed tomography for volumetric analysis (retrospective development cohort: 1146 patients; prospective validation cohort: 207 patients). Semiautomated software assessed tICH expansion (defined as ≥33% or 5 mL absolute growth). MLR was acquired from routine blood tests upon admission. We constructed two predictive models: basic combined model of clinical and imaging variables and MLR combined model of both MLR and other variables in the basic model. Receiver operating characteristic (ROC) analysis and decision curve analysis (DCA) were used to estimate the performance of MLR for predicting acute tICH expansion. Results. MLR was significantly larger in patients with acute tICH expansion compared to those without acute tICH expansion (mean [SD], 1.08 [1.05] vs. 0.59 [0.37], ). A nonlinear positive relationship between MLR and the incidence of acute tICH expansion was observed. Multivariate logistic regression indicated MLR as an independent risk factor for acute tICH expansion (odds ratio (OR), 5.88; 95% confidence interval (CI), 4.02-8.61). The power of the multivariate model for predicting acute tICH expansion was substantially improved with the inclusion of MLR (AUC 0.86 vs. AUC 0.74, ), as was also observed in an external validation cohort (AUC 0.83 vs. AUC 0.71, ). The net benefit of MLR model was higher between threshold probabilities of 20-100% in DCA. For clinical application, a nomogram derived from the multivariate model with MLR was introduced. In addition, MLR was positively associated with 6-month unfavorable outcome. Conclusion. MLR is a novel predictor for traumatic parenchymatous hematoma expansion. A nomogram derived from the MLR model may provide an easy-to-use tool for predicting acute tICH expansion and promoting the individualized treatment of patients with hemorrhagic cerebral contusion. MLR is associated with long-term outcome after cerebral contusion.

Traumatic brain injury (TBI) represents a critical public health challenge with profound consequences for patients’ neurological function and quality of life. The delayed secondary injuries following TBI can lead to devastating long-term sequelae encompassing cognitive deficits, emotional disturbances, post-traumatic epilepsy, and neurodegeneration manifested as Alzheimer’s disease or Chronic Traumatic Encephalopathy (CTE). Emerging evidence highlights neuroinflammation as a pivotal mechanism driving secondary injury progression, establishing it as a prime therapeutic target in TBI management. Central to this process is the dysregulated cytokine release and associated signaling cascades that orchestrate neuroinflammatory responses. The pathological persistence of neuroinflammation arises from chronic glial activation and sustained immune cell infiltration following TBI. This review systematically examines recent advances in understanding cytokine dynamics and their regulatory pathways across different temporal phases of TBI-induced neuroinflammation. Notably, cytokines exhibit temporal functional pleiotropy - the same inflammatory mediators may exert diametrically opposed effects during acute (7d) post-injury phases. This temporal dichotomy underscores the critical importance of precision timing when implementing cytokine-targeted therapies. Our comprehensive analysis integrates current clinical, preclinical and basic research evidence to illuminate potential mechanisms underlying TBI-associated neuropathology. We propose that multi-modal therapeutic strategies should combine spatiotemporal regulation of cytokine activity with pathway-specific interventions. This approach could potentially disrupt the self-perpetuating cycle of neuroinflammation while preserving beneficial reparative functions. The synthesis presented herein provides a framework for developing chronotherapeutic interventions against TBI-related neural dysfunction.

Influenza A viruses (IAV), significant respiratory pathogenic agents, cause seasonal epidemics and global pandemics in intra- and interannual cycles. Despite effective therapies targeting viral proteins, the continuous generation of drug-resistant IAV strains is challenging. Therefore, exploring novel host-specific antiviral treatment strategies is urgently needed. Here, we found that lidocaine, widely used for local anesthesia and sedation, significantly inhibited H1N1(PR8) replication in macrophages. Interestingly, its antiviral effect did not depend on the inhibition of voltage-gated sodium channels (VGSC), the main target of lidocaine for anesthesia. Lidocaine significantly upregulated early IFN-I, interferon α4 (IFNα4) mRNA, and protein levels, but not those of early IFNβ in mouse RAW 264.7 cell line and human THP-1 derived macrophages. Knocking out IFNα4 by CRISPR-Cas9 partly reversed lidocaine's inhibition of PR8 replication in macrophages. Mechanistically, lidocaine upregulated IFNα4 by activating TANK-binding kinase 1 (TBK1)-IRF7 and JNK-AP1 signaling pathways. These findings indicate that lidocaine has an incredible antiviral potential by enhancing IFN-I signaling in macrophages. In conclusion, our results indicate the potential auxiliary role of lidocaine for anti-influenza A virus therapy and even for anti-SARS-CoV-2 virus therapy, especially in the absence of a specific medicine.

Accurate and convenient serological markers for prognosis after traumatic brain injury (TBI) are still lacking. We aimed to explore the predictive value of serum calcium for prognosing outcomes within 6 months after TBI. In this multicenter retrospective study, 1255 and 719 patients were included in development and validation cohorts, respectively, and their 6-month prognoses were recorded. Serum calcium was measured through routine blood tests within 24 h of hospital admission. Two multivariate predictive models with or without serum calcium for prognosis were developed. Receiver operating characteristics and calibration curves were applied to estimate their performance. The patients with lower serum calcium levels had a higher frequency of unfavorable 6-month prognosis than those without. Lower serum calcium level at admission was associated with an unfavorable 6-month prognosis in a wide spectrum of patients with TBI. Lower serum calcium level and our prognostic model including calcium performed well in predicting the 6-month unfavorable outcome. The calcium nomogram maintained excellent performance in discrimination and calibration in the external validation cohort. Lower serum calcium level upon admission is an independent risk factor for an unfavorable 6-month prognosis after TBI. Integrating serum calcium into a multivariate predictive model improves the performance for predicting 6-month unfavorable outcomes.