Diabetes mellitus exacerbates cerebral ischemic damage by potentiating neuroinflammation. We hypothesized that activation of the bradykinin type 2 receptor, a mediator of inflammation and vascular dynamics, might be detrimental to ischemic injury development in diabetic animals. We monitored the acute phase of cerebral ischemia in type 1 diabetic mice, diabetic bradykinin type 2 receptor knock-out mice, and their non-diabetic controls using neurological assessment, magnetic resonance imaging, and a comprehensive immuno-histochemical and morphological analysis to quantify changes in microglial, neutrophil, and neuronal populations. Our findings reveal that bradykinin type 2 receptor deficiency ameliorates neurological deficit in non-diabetic mice, despite similar ischemic lesion volumes across all investigated groups. Furthermore, in non-diabetic animals, the bradykinin type 2 receptor plays a discernible role in edema resolution, neuroprotection, and regulation of microglial response to ischemia. However, diabetes, as a stroke comorbidity, alters the involvement of the bradykinin type 2 receptor in ischemic injury development. Bradykinin type 2 receptor-deficient diabetic animals demonstrate delayed microglial cell loss and reduced microglial reactivity following ischemia compared to diabetic animals with functional bradykinin type 2 receptors. The attenuated immune response is accompanied by a marked absence of infiltrating neutrophils within the ischemic territory and improved neuronal survival. This study demonstrates that diabetes profoundly modifies the role of bradykinin type 2 receptor in cerebral ischemic injury, influencing both acute neuroinflammation and cell survival. These findings support the potential of the bradykinin type 2 receptor as a therapeutic target for stroke in diabetic population, warranting further investigation.

Neuropathic pain is a chronic pain condition characterized by complex pathogenesis and poor prognosis. EB (Eupalinolide B), a highly bioactive sesquiterpene lactone derived from Eupatorium lindleyanum DC, has been demonstrated to possess multiple pharmacological activities, including antihistamine, antibacterial, and antioxidant effects. USP7 (ubiquitin-specific protease 7) is a crucial deubiquitinating enzyme in eukaryotes, while the Keap1, Nrf2, and HO-1 signaling pathways play pivotal roles in the development of neuropathic pain. Our study established a spared nerve injury model in mice and employed multiple molecular biology experiments to investigate the regulatory role of EB in the USP7/Keap1/Nrf2 pathway and its mechanisms in neuropathic pain. Results showed significantly elevated USP7 and Keap1 protein expression in the spinal cord of SNI mice, while Nrf2 and HO-1 levels were markedly reduced. EB treatment downregulated USP7 expression, promoted Keap1 ubiquitination and degradation, thereby elevating Nrf2/HO-1 protein levels. This inhibited microglial proliferation and M1 polarization, reduced the production of proinflammatory factors (TNF-α, IL-1β, IL-6), and significantly ameliorated mechanical and thermal hyperalgesia in SNI mice. Long-term intraperitoneal injection of EB did not cause any significant side effects in the heart, liver, or kidneys of SNI mice. In summary, EB exerts anti-inflammatory and analgesic effects by modulating the USP7/Keap1/Nrf2 signaling pathway, offering a potential novel therapeutic strategy for neuropathic pain.

High mobility group box 1 (HMGB1), a nuclear protein, once released to the extracellular space, participates in the pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN). Thrombomodulin alfa (TMα), a recombinant soluble protein of endothelial thrombomodulin, prevents CIPN by promoting thrombin-dependent HMGB1 degradation and activation of protein C and thrombin-activatable fibrinolysis inhibitor (TAFI/plasma carboxypeptidase B/CPB2). We thus investigated the downstream molecules of activated protein C (APC) and TAFI (TAFIa), for prevention of oxaliplatin-induced peripheral neuropathy (OIPN) in mice. OIPN was prevented by TMα and by each of an anti-HMGB1-neutralizing antibody (HAb), APC and porcine pancreatic carboxypeptidase B (ppCPB, used as a stable surrogate of TAFIa), or their combination at subeffective doses. Intraplantar administration of HMGB1 induced mechanical allodynia, which was abolished by TMα, but not APC or ppCPB. The anti-OIPN effects of TMα and APC were reversed by an antagonist of proteinase-activated receptor 1 (PAR1), targetable by APC, and the effect of TMα was also reversed by a CPB inhibitor. Intraplantar administration of mouse C5a (mC5a), targetable by TAFIa, caused mechanical allodynia, an effect blocked by TMα, a mC5a receptor (mC5aR) antagonist or HAb. The mC5aR antagonist prevented OIPN development. Oxaliplatin significantly increased plasma C5a levels in the mice treated with argatroban, a thrombin inhibitor, capable of reducing the degradation of HMGB1 by the endogenous thrombin-thrombomodulin axis. Our data thus suggest that the anti-OIPN effect of TMα involves APC-induced PAR1 activation and TAFIa-induced degradation of C5a that induces HMGB1-dependent pain, in addition to HMGB1 degradation.

Cerebral ischemia-reperfusion (I/R) injury is a critical condition leading to severe neurological deficits. Inflammation, driven by microglial polarization, plays a significant role in the progression of I/R injury. Gallic acid (GA), a natural polyphenol, has been recognized for its anti-inflammatory and neuroprotective properties. Male mice subjected to middle cerebral artery occlusion (MCAO) were treated with GA. Neurological deficits, infarct size, and brain edema were assessed to evaluate the neuroprotective effects of GA. In vitro, oxygen-glucose deprivation/reoxygenation (OGD/R) models were used to simulate I/R injury in microglial cells. The polarization of microglia was analyzed by flow cytometry, qPCR, and Western blot, focusing on M1 and M2 markers. Autophagy and inflammasome activation were investigated using Western blot, immunofluorescence, and flow cytometry, with the effects of GA modulated by autophagy and inflammasome inhibitors. GA treatment significantly improved neurological outcomes in MCAO mice by reducing infarct size, brain edema, and promoting the M2 polarization of microglia while inhibiting M1 polarization. GA enhanced autophagy and suppressed NLRP3 inflammasome activation via the mTOR pathway, reducing pro-inflammatory cytokine expression. Inhibition of autophagy reversed the protective effects of GA, leading to increased M1 polarization and exacerbated neuroinflammation. Additionally, activation of the NLRP3 inflammasome counteracted GA's effects, emphasizing the role of this pathway in microglial modulation. GA exerts neuroprotective effects in cerebral I/R injury by modulating microglial polarization through the NLRP3/mTOR axis. Its ability to promote autophagy and suppress inflammasome activation positions GA as a potential therapeutic agent for reducing neuroinflammation and improving outcomes in I/R injury.

Emerging evidence links zinc dyshomeostasis to the pathogenesis of Parkinson's disease (PD), highlighting the need to explore zinc-based interventions. Zinc has five stable isotopes, with Zn and Zn being the most abundant. Notably, healthy brain tissue is enriched in the lighter isotope Zn, while heavier isotopes are hypothesized to accumulate with age. This study examined the therapeutic potential of intravenously administered isotopically enriched Zn aspartate (Zn-asp) in a rat model of PD induced by a single stereotactic intranigral injection of lipopolysaccharide (LPS, 10 μg), which simulates acute neuroinflammation followed by progressive neurodegeneration. Treatment effects were evaluated using behavioral assessments, immunological profiling, biochemical and molecular analyses, and histopathology. Rats treated with Zn-asp showed a pronounced anti-inflammatory shift in microglial/macrophage metabolic profiles and reduced reactive astrogliosis. These changes were accompanied by improved motor performance and decreased anxiety-like behavior. Immunohistochemistry confirmed preservation of dopaminergic neurons. Overall, these findings suggest that Zn-asp attenuates neuroinflammation and supports neuronal survival, indicating its potential as a candidate for disease-modifying strategies in PD.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin (HTT) gene. It typically manifests as a triad of progressive psychiatric, cognitive, and motor symptoms. The resulting mutant HTT (mHTT) protein disrupts cellular homeostasis and promotes neuroinflammation. The NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome is a key mediator of neuroinflammatory responses, activating caspase-1 and promoting the release of interleukin (IL)-1β and IL-18. In this study, we investigated the neuroprotective potential of glucosamine (GlcN) in HD. Our results demonstrate that GlcN effectively attenuates lipopolysaccharide (LPS)/ATP-induced NLRP3 inflammasome activation in BV2 microglia, leading to a significant reduction in IL-1β and IL-18 secretion. Mechanistically, GlcN suppresses microglial activation by inhibiting the mitogen-activated protein kinase (MAPK) signaling pathway, thereby reducing nuclear factor-κB (NF-κB) activation. In the R6/2 transgenic mouse model of HD, oral administration of GlcN significantly enhanced neuronal survival, reduced mHTT aggregation, suppressed NLRP3 inflammasome activation, and attenuated astrocytic and microglial activation. Furthermore, GlcN improved motor performance and extended the lifespan of R6/2 mice. These findings suggest that GlcN confers neuroprotection in HD by attenuating neuroinflammation through inhibition of the NLRP3 inflammasome. Our study shows that GlcN is an effective treatment candidate for HD by targeting neuroinflammatory pathways, particularly through inhibition of the NLRP3 inflammasome, thereby presenting a promising strategy to slow disease progression.

Chemotherapy-induced neuropathic pain (CINP) affects up to 80% of cancer patients treated with cytostatic drugs like paclitaxel (PTX), leading to significant chronic sensorimotor dysfunction. Current pharmacological treatments often cause CNS side effects such as sedation and addiction. Increasing evidence indicates that native µ- and δ-opioid receptors (ORs) can associate to form heteromers in discrete brain regions. However, the role of µ-δ heteromer in CINP remains unclear. Therefore, we investigated the analgesic activity of CYM51010, a µ-δ heteromer agonist in CINP and how µ-δ heteromer activation regulates neuropathic pain. Systemic CYM51010 administration significantly alleviated evoked and ongoing pain in CINP mice, without inducing drug-seeking behavior, unlike morphine, which was consistent with earlier findings observed in SNL rats. Molecular analysis revealed that CYM51010 significantly decreased the increased TRPV1 and p38α expression in the dorsal root ganglion as well as spinal tissues of CINP mice. CYM51010 also reduced the expression of NF-κB, microglial markers (ICAM-1 & IBA1), and pro-inflammatory cytokines (TNF-α, IL-1β). Findings from the current study indicate that µ-δ heteromer activation represents a promising therapeutic target for chemotherapy-induced neuropathic pain (CINP), potentially enabling effective pain relief with reduced central side effects.

Ubiquitination is a key enzymatic process where ubiquitin molecules covalently attach to substrate proteins, regulating their degradation, trafficking, and signaling. This process ensures cellular homeostasis by controlling protein quality and abundance, and it plays a vital role in immunity, DNA repair, and the cell cycle. Further, ubiquitination involves a sophisticated network of enzymes, domains, and receptors, providing pathway flexibility. However, dysregulation of ubiquitination due to aberrant enzyme function is implicated in various disorders, including cancer, diabetes, stroke, and neurodegenerative diseases (NDDs). Additionally, the ubiquitin-proteasome system (UPS) not only mediates protein degradation but also influences inflammation and subcellular localization. This review explores the pivotal role of ubiquitination and deubiquitination enzymes in the onset and progression of NDDs. It highlights their involvement in protein aggregation, mitochondrial impairment, neuroinflammation, and altered synaptic function. Special focus is placed on mutations in E3 ligases (e.g., E3 ubiquitin ligase encoded by PARK2 (Parkin), C-terminus of Hsp70-interacting protein (CHIP)) and deubiquitinases (e.g., USP14, ubiquitin C-terminal hydrolases (UCHL1)), which disrupt proteostasis and lead to the accumulation of neurotoxic proteins, such as Aβ, tau, α-synuclein, and mHtt. Moreover, post-translational modifications (PTMs), including phosphorylation, acetylation, and oxidative stress, further modulate UPS activity and disease progression. Lastly, the review also evaluates emerging therapeutic strategies aimed at restoring proteostasis, including proteasome-targeting small molecules (e.g., bortezomib, IU1-47), natural compounds (e.g., curcumin, resveratrol), RNA-based therapies (e.g., miR-101, circHIPK3), and dietary approaches (e.g., Mediterranean and ketogenic diets), offering a foundation for future neurodegenerative disease treatment.

Ischaemic stroke is the leading cause of long-term cognitive impairments, affecting brain regions vulnerable to memory and learning, with complex and diverse mechanisms. The hippocampus along with cortex is crucial for shaping essential cognitive functions in post-stroke cognitive impairments. However, the region-specific neural, molecular and cellular mechanistic response to ischaemic-damage, particularly the role of inflammation is rarely explored. In this context, we carried out post-stroke region-specific research, including the development of BCCAo model and the neurobehavioral assessment targeting memory and learning deficits. Here, we performed NGS and depth-in-network analysis of the isolated cortical and hippocampal regions of the post-stroke BCCAo model, revealing 13 significant neurodegenerative hub genes including Map2k6 and Mapk11, which play crucial roles in inflammation-mediated post-stroke neurodegenerative cascades. Significant upregulation of MAP2K6/MAPK11 in the cortex of ischaemia-treated rats was observed, whereas its comparatively diminished expression in the hippocampus demand exploration of region-specific study in chronic ischaemic conditions. Furthermore, we demonstrated the role of MAPK11 as neuroinflammatory regulator and alleviating the cognitive impairments by including the upstream Akt/GSK3β pathway components. Our findings not only highlighted the potential roles of MAP2K6/MAPK11 driving neuroinflammatory processes regulating ischaemic cascades but also pinpointed the hippocampus's relative resilience preserving cognitive function. Targeting MAPK11 and its associated neuroinflammatory pathways in the cortex to mitigate PSCI holds promise as a therapeutic strategy in chronic ischaemia.

Alzheimer's disease (AD) is the most common form of dementia, characterized by a progressive decline in cognitive functions. It is more prevalent in women, especially after menopause, likely due to factors like longer life expectancy and hormonal changes. Current therapies focus on cholinesterase inhibitors, but recent studies suggest that pyrimidine derivatives hold promise as multi-target agents targeting complex mechanisms of AD. This study evaluated the potential of a pyrimidine derivative, (E)-N-[4-(4-chlorophenyl)-6-(4-methylphenyl)pyrimidin-2-yl]-1-(furan-2-yl)methanimine (named BN5), in a scopolamine (SCO)-induced female zebrafish model. SCO induces cognitive dysfunction mimicking AD conditions. BN5, particularly at a 60 µM concentration, significantly improved AD-related parameters, including anxiety, memory, shoaling, and social behaviour in vivo. Biochemical analyses supported these findings, as BN5 reversed SCO-induced changes in acetylcholinesterase (AChE) activity and oxidative stress markers, such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), glutathione peroxidase (GPx), malondialdehyde (MDA), and γ-Aminobutyric acid (GABA) levels. Additionally, BN5 demonstrated positive regulation of neurotransmitter-related genes such as appb, bdnf, mbpa, and il-1β, essential for neural function and cognitive processes. It also upregulated estrogen receptor genes esr1 and esr2b, which have neuroprotective roles but are often downregulated in postmenopausal women due to hormonal changes. These results highlight the therapeutic potential of BN5, as it alleviates cognitive impairments through Aβ aggregation inhibition and addresses the decline in estrogen receptor activity, providing a targeted treatment option particularly beneficial for females, who are at greater risk of developing AD.

Estrogen deficiency in postmenopausal women disrupts reproductive, metabolic, brain, and gut health, partly by promoting inflammation, oxidative stress, and gut dysbiosis. Together, responsible for the development of gut-brain axis (GBA) dysfunction. Daily life stressors in women, particularly chronic stress, may further exacerbate this dysfunction; however, their synergistic effects with estrogen deficiency remain poorly understood. The current study aimed to develop an animal model of GBA dysfunction that mimics postmenopausal conditions. To induce GBA dysfunction, female Sprague Dawley rats were bilaterally ovariectomized (OVX) and exposed to chronic unpredictable mild stress (CUMS) for 28 days. To confirm GBA dysfunction, neurobehavioral, biochemical, molecular, and histopathological parameters were performed. We observed significant changes in physiological, & neurobehavioral parameters in OVX, CUMS, and OVX + CUMS group rats. We also observed marked enhancement in oxidative stress, neuroinflammation, and reduced acetylcholinesterase activity in the brain, and increased corticosterone levels in serum of OVX, CUMS, and OVX + CUMS group rats. Furthermore, we also observed a marked increase in pro-inflammatory cytokines, oxidative stress, reduction in MUC-2 and tight junction gene expression in the proximal colon, and changes in gut bacterial abundances in the feces of experimental groups. Histopathological examination revealed pronounced morphological damage in the proximal colon and brain of OVX, CUMS, and OVX + CUMS group rats. Thus, estrogen deficiency and chronic stress for one month synergistically induce GBA dysfunction. This developed animal model provides a robust platform for exploring novel therapeutic strategies to counteract GBA dysfunction arising from estrogen deficiency and chronic stress.

Glioblastoma is a grade 4 diffuse astrocytic glioma that is the most aggressive brain malignancy, with poor treatment outcomes and median overall survival (OS) of 10-14 months. Glioblastoma is characterized by upregulation of NAD metabolism, required to maintain rapid proliferation and DNA repair. Nicotinamide phosphoribosyltransferase (NAMPT), is the rate limiting enzyme in the NAD salvage pathway, and has emerged as a promising target in the treatment of glioblastoma. Previously, we reported the crucial role of adaptor protein TRAF3IP2 in glioblastoma tumorigenesis. In this study, we aim to investigate the role of TRAF3IP2 in modulating NAMPT expression and explore its downstream impact on promoting cellular energetics in glioblastoma cells. Our results reveal that inhibition of TRAF3IP2 in glioblastoma cells attenuates metabolic activity, as evidenced by decreased expression levels of NAMPT and the mTOR complex, leading to reduction in NAD synthesis and glycolytic function, decreased expression of NAD-dependent deacetylase SIRT1, and increased presence of cellular ROS and expression of tumor suppressor p53, cumulatively resulting in decreased cell viability in glioblastoma. These outcomes elucidate that inhibition of TRAF3IP2 exerts significant anti-tumor effects on glioblastoma by reducing NAD availability and cancer-cell metabolism, highlighting the therapeutic potential of TRAF3IP2 in glioblastoma.

Emerging evidence suggests brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a proposed pathogenic mechanism in HIV-associated neurocognitive disorders (HAND). We investigated whether cannabinoid receptor 2 (CB), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB-specific agonist JWH-133, we found that CB activation reduced HIV replication in primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg) at differing doses, corresponding to the basal expression of CNR2, which encodes CB, and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced release of cytokines from HIV-infected MDMs but not iMg. RNA-seq revealed that CB agonism primarily altered interferon and integrated stress response pathways in MDMs while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB response between myeloid lineage cell types and implicates CB-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.

Patients admitted for surgery commonly experience preoperative anxiety. Previous studies have shown that preoperative anxiety often delays recovery from postoperative pain or even aggravates pain. Therefore, it is necessary to explore the mechanisms by which anxiety prolongs chronic postoperative pain. A single prolonged stress (SPS) rat model was constructed to investigate the effects of anxiety and depression using behavioral tests. Changes in the levels of tight junction proteins in the cerebral striatum (CPu) of the rats were assessed by western blotting 1 to 21 days after the operation. The level of inflammation was detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Glucose metabolism levels and changes in related signaling pathways in microglia were assessed using western blotting, immunofluorescence, ELISA, and flow cytometry. The effects of S-ketamine treatment on the rats were also determined using the above methods. Preoperative SPS aggravated acute pain after plantar incision in rats and significantly prolonged the postoperative pain recovery time. The incised SPS rats began to show significant blood-brain-barrier (BBB) damage on the third day after surgery. Simultaneously, SPS caused neuroinflammation and microglial activation in the CPu after plantar incision. CPu microglia participated in neuroinflammation by undergoing glucose metabolic reprogramming mediated by the mTOR-p70S6K-4EBP1 pathway. Preoperative administration of a single dose of S-ketamine was an effective analgesic, as it inhibited SPS-induced postoperative inflammation. S-ketamine partially corrected SPS-induced abnormal glycolysis in striatal microglia through the mTOR-p70S6K-4EBP1 pathway. S-ketamine effectively relieved postoperative chronic pain caused by preoperative anxiety by correcting glucose metabolic reprogramming in CPu microglia.

Gliomas are the most common primary brain tumors and characterized by poor prognosis and heavy infiltration of tumor-associated macrophages. Triggering receptor expressed on myeloid cells-2 (TREM2), known to modulate macrophage function, has shown conflicting roles in glioma pathology. In this study, we comprehensively investigated the expression, function, and clinical relevance of TREM2 in gliomas using public datasets, single-cell RNA sequencing (scRNA-seq) analysis, and multiplex immunofluorescence. scRNA-seq identified a distinct subset of microglia-derived macrophages with high TREM2 expression that exhibit a dual phenotype of immunosuppression and enhanced lipid metabolism. These cells show enrichment of genes involved in fatty acid metabolism and lipoprotein clearance, including significant upregulation of apolipoprotein E (APOE), a known TREM2 ligand. Clinically, high TREM2 expression in microglia-derived macrophages correlates with increased tumor grade, recurrence, and shorter overall and disease-free survival. In contrast, APOE expression was correlated with better survival in public datasets, though not significantly in our patient cohort. Our findings suggest that TREM2 microglia-derived macrophages constitute a pro-tumorigenic subpopulation within the glioma microenvironment and may serve as a robust prognostic marker. The interplay between TREM2 and APOE further underscores the immunometabolic complexity of gliomas and points to TREM2 as a promising target for therapeutic intervention.

Parkinson's disease (PD), the second most prevalent neurodegenerative disorder, remains without a curative pharmacological intervention. Sea Cucumber Peptides (SCP) are recognized for their antioxidant properties and neuroprotective potential, while no specific SCP have been documented for PD treatment. Moreover, sea cucumbers have long been consumed as a traditional food; viewed through the lens of "food-medicine homology", their peptides possess clear pharmaceutical potential. This study sets out to pinpoint particular peptide sequences from sea cucumbers could combat PD, exploring their therapeutic efficacy and the underlying mechanisms. We treated Rotenone (Rot)-induced C57BL/6 J mice and SH-SY5Y cells with the SCP which were extracted from the sea cucumbers, to assess the impact on behavioral metrics in mice, histopathological outcomes, cellular viability, and in vitro bioactivity. Employing a combination of peptide profiling and silico analysis, we established a SCP spectrum to identify novel SCP with potential anti-PD activity. The therapeutic effects and mechanisms of the peptides were further investigated in 7-day-old zebrafish larvae and SH-SY5Y cells exposed in Rot, respectively. Our findings indicate that the SCP significantly improved behavioral deficits in mice, reduced the degeneration of dopaminergic neurons in the substantia nigra, and increased the survival of Rot-exposed SH-SY5Y cells. Notably, a novel peptide, Gln-Trp-Phe-Asp-Trp (QWFDW), emerged from our peptide profiling and in silico analysis, showing significant anti-PD activity. QWFDW was demonstrated to enhance the behavioral performance of Rot-induced zebrafish larvae, and ameliorate the pathological features of PD by attenuating endogenous reactive oxygen species (ROS) and maintaining mitochondrial membrane potential in SH-SY5Y cells. At the cellular level, QWFDW activates the Nrf2/HO-1/GPX4 pathway to alleviate ferroptosis and exert therapeutic effects on PD. Collectively, our results point out that SCP, particularly QWFDW, was a prospective therapeutic agent for PD.

High mobility group box 1 (HMGB1), a nuclear protein, once released extracellularly, exists in two different active forms, i.e., all-thiol (at)- and disulfide (ds)-HMGB1. Given that HMGB1 promotes neuritogenesis, we examined whether at/ds-HMGB1 would promote neuritogenesis in dorsal root ganglion (DRG) neurons, and participate in regeneration priming of DRG neurons by sciatic nerve crush (SNC). In cultured mouse DRG neurons, at-HMGB1, but not ds-HMGB1, accelerated neuritogenesis, an effect blocked by an antagonist of receptor for advanced glycation end-product (RAGE). A combination of thrombin and thrombomodulin alfa (TMα) capable of sequestering HMGB1 with its D1 domain and promoting HMGB1 degradation by thrombin tethered to its D2 domain synergistically suppressed the at-HMGB1-induced neuritogenesis, an effect abolished by angiopoietin-1 capable of inhibiting the binding of thrombin to TMα. The DRG neurons from the mice subjected to SNC exhibited accelerated neuritogenesis, even in the presence of an anti-HMGB1-neutralizing antibody (HMGB1-Ab). However, the neurite regeneration priming of DRG neurons by SNC in mice was prevented by daily treatment with HMGB1-Ab, minocycline, a macrophage/microglia inhibitor, ethyl pyruvate capable of inhibiting HMGB1 release from macrophages, and azeliragon, a RAGE antagonist. SNC caused macrophage accumulation in the sciatic nerves, but not DRG. Our data suggest that extracellular at-HMGB1 causes RAGE-dependent acceleration of neuritogenesis in cultured DRG neurons, which is suppressed synergistically by thrombin and TMα. Nonetheless, neurite regeneration priming of DRG neurons by SNC is considered to involve HMGB1 derived from macrophages recruited to the damaged axon, but is not mediated by HMGB1 released from cultured DRG cells.

Neurological adverse effects are frequent, primarily non-serious, due to the tropism of COVID 19 adverse effects for neuronal structures and tissues. To our knowledge, there are no studies on neurological adverse effects of COVID-19 vaccines in Burkina Faso. The purpose of this study was to determine the prevalence of neurological side effects of COVID-19 vaccines, to catalogue neurological adverse effects, to describe these manifestations, and to identify factors associated.

Treatment options for progressive MS (PMS) are limited in numbers and efficacy, which is most pronounced in patients with inflammatory disease activity. Immunoglobulin M (IgM) oligoclonal bands (OCBs) may identify a subset of PMS with more active inflammatory disease. The effects of natalizumab and methylprednisolone on intrathecal inflammation and the association of IgM OCBs with other biomarkers in PMS is uncertain. In the current study, we investigated the cerebrospinal fluid (CSF) proteome of untreated patients with PMS, effects of natalizumab and methylprednisolone, and associations of IgM OCBs with disease activity and CSF biomarkers. We found a reduction of BCMA, SLAMF7, granzyme A, IgG, and desmoglein-2 with both therapies, as well as natalizumab-specific reductions of VCAM-1, CD48, MDC, MMP-9, sE-selectin, and CHIT1, and methylprednisolone-specific reductions of DR3, IgD, RTN4, and increases of sCD206, LYVE1, sCD163 and MMP-3. IgM OCBs were associated with reduced levels of PIGR, higher levels of NFL and VEGF, and more contrast-enhancing lesions. The study suggests T and B cell activity biomarkers as treatment-responsive CSF biomarkers in PMS. Additionally, we found natalizumab to reduce adhesion molecules and methylprednisolone to increase myeloid biomarkers. Lastly, we confirm that IgM OCBs are associated with a more inflammatory MRI and CSF profile.

HMGB1-mediated neuroinflammation assumes a pivotal position in the pathophysiological framework of a multitude of neurological disorders, including ischemic stroke, which still urgently need effective therapeutic agents. CDDO-Me, is a potentially useful therapeutic drug for diabetic nephropathy, whereas the neuroprotective properties and underlying mechanism in ischemic stroke have not been reported as yet. In the present study, CDDO-Me was found to alleviate OGD/R induced nerve cell injury and protect the cerebral ischemia of rats. In addition, the proinflammatory activity of HMGB1 was inhibited by CDDO-Me through directly binding to HMGB1 and then disrupting its interaction with receptor TLR4. The binding affinity of CDDO-Me to HMGB1 was 117 µM indicated by surface plasmon resonance (SPR) assay. On this basis, we observed that CDDO-Me could slightly change the secondary and steric conformation as well as the thermal stability of HMGB1. Subsequently, molecular dynamics (MD) simulation showed that CDDO-Me mainly binds to the A-box domain of HMGB1, which was maintained by weak interaction forces like van der Waals and hydrophobicity. Further virtual mutagenesis and binding free energy calculations identified F38 and F89 in the A-box as key residues involved in HMGB1-CDDO-Me interaction. These findings indicated that CDDO-Me can improve stroke-induced inflammatory damage through direct binding HMGB1 and negative regulation of HMGB1-TLR4 downstream cytokine signaling activity.