Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology最新文献

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.

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.

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 ⁶⁴Zn and ⁶⁶Zn being the most abundant. Notably, healthy brain tissue is enriched in the lighter isotope ⁶⁴Zn, while heavier isotopes are hypothesized to accumulate with age. This study examined the therapeutic potential of intravenously administered isotopically enriched ⁶⁴Zn aspartate (⁶⁴Zn-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 ⁶⁴Zn-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 ⁶⁴Zn-asp attenuates neuroinflammation and supports neuronal survival, indicating its potential as a candidate for disease-modifying strategies in PD.

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.

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.

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.

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.

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.