Spinal Cord Inflammation Research Articles

HUCMSC-derived exosomes mitigate blood-spinal cord barrier disruption by activating AMPK/mTOR-mediated autophagic flux after acute spinal cord injury

After spinal cord injury (SCI), the integrity of the blood-spinal cord barrier (BSCB) can be disrupted, leading to the secondary injuries such as inflammatory cell infiltration, neuronal death, and spinal cord hematoma. It is important to maintain the integrity of the BSCB to help restore function following SCI. While some studies have demonstrated the therapeutic effects of exosomes derived from human umbilical cord mesenchymal stem cells (hUCMSC-exos), their role in preserving BSCB integrity remains unclear. In our study, we demonstrated the protective effects of hUCMSC-exos on the BSCB and its mechanism. The results of this study indicate that hUCMSC-exos promote motor function recovery, preserve spinal cord structure, and reduce neuronal loss by inhibiting BSCB leakage following SCI. Experimental investigations conducted in vivo and in vitro have demonstrated that hUCMSC-exos can mitigate the loss of adherens junctions (AJs) and tight junctions (TJs) and stimulate autophagy in spinal cord endothelial cells. The protective effects were also found to be significantly reversed following the inhibition of autophagy using 3-MA. In conclusion, our study demonstrates that hUCMSC-exos protect the integrity of BSCB by promoting the repair of spinal endothelial cells through activation of autophagy, thereby exerting a protective role in SCI.

Constructing Electron-Rich Ru Clusters on Non-Stoichiometric Copper Hydroxide for Superior Biocatalytic ROS Scavenging to Treat Inflammatory Spinal Cord Injury.

Traumatic spinal cord injury (SCI) represents a complex neuropathological challenge that significantly impacts the well-being of affected individuals. The quest for efficacious antioxidant and anti-inflammatory therapies is both a compelling necessity and a formidable challenge. Here, in this work, the innovative synthesis of electron-rich Ru clusters on non-stoichiometric copper hydroxide that contain oxygen vacancy defects (Ru/def-Cu(OH)2), which can function as a biocatalytic reactive oxygen species (ROS) scavenger for efficiently suppressing the inflammatory cascade reactions and modulating the endogenous microenvironments in SCI, is introduced. The studies reveal that the unique oxygen vacancies promote electron redistribution and amplify electron accumulation at Ru clusters, thus enhancing the catalytic activity of Ru/def-Cu(OH)2 in multielectron reactions involving oxygen-containing intermediates. These advancements endow the Ru/def-Cu(OH)2 with the capacity to mitigate ROS-mediated neuronal death and to foster a reparative microenvironment by dampening inflammatory macrophage responses, meanwhile concurrently stimulating the activity of neural stem cells, anti-inflammatory macrophages, and oligodendrocytes. Consequently, this results in a robust reparative effect on traumatic SCI. It is posited that the synthesized Ru/def-Cu(OH)2 exhibits unprecedented biocatalytic properties, offering a promising strategy to develop ROS-scavenging and anti-inflammatory materials for the management of traumatic SCI and a spectrum of other diseases associated with oxidative stress.

Atractylenolide-I Ameliorates Motor Deficits and Reduces Inflammation of the Spinal Cord by SIRT1/PGC-1α Pathway in MPTP Subacute Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative movement disorder that impacts various systems, including the substantia nigra (SN) par compacta (SNpc) and extranigral regions like the spinal cord. The presence of persistent inflammation in the SN and spinal cord is associated with movement difficulties in PD. Atractylenolide-I (ATR-I) is a natural sesquiterpene recognized for its anti-inflammatory and neuroprotective effects. This research aimed to assess the impact of ATR-I treatment on motor function and inflammation in MPTP-induced subacute PD mice, particularly focusing on the role of ATR-I in spinal cord inflammation. The motor functions of the mice were assessed using suspension and gait tests. Dopaminergic neuronal loss in the SNpc and microglial activation in both the SNpc and spinal cord were evaluated through immunofluorescence staining. The levels of inflammatory mediators in the spinal cord were measured using RT-qPCR analysis. The expressions of SIRT1 and PGC-1α in the spinal cord were analyzed through Western blotting and RT-qPCR. ATR-I treatment improved motor deficits in MPTP-induced mice. Moreover, ATR-I reduced the loss of dopamine neurons and microglial activation in the SNpc of MPTP-induced mice. Additionally, ATR-I suppressed spinal cord inflammation by decreasing microglial activation and the mRNA expression of TNF-α, IL-1β, and iNOS in MPTP-induced mice. Interestingly, ATR-I also upregulated SIRT1 and PGC-1α levels in the spinal cord of MPTP-induced mice. These findings suggest that ATR-I exhibits anti-inflammatory and neuroprotective properties in PD. The attenuation of spinal cord inflammation via the SIRT1/PGC-1α pathway may contribute to enhancing motor function, highlighting ATR-I as a potential therapeutic avenue for PD.

The Impact of Caffeic Acid Phenethyl Ester on Spinal Cord Inflammation in Mice Model of Multiple Sclerosis

Since the majority of the current therapies lack effectiveness and efficiency in treating Multiple Sclerosis, in addition to their high cost, monitoring during usage, and the serious side effects associated with using this therapy, which in some cases may be fatal, for these reasons, there is a necessary need for effective therapy in the clinical setting and searching for an alternative therapy that is effective and safe. For this purpose, this study evaluated the impact and efficiency of Caffeic acid phenethyl ester(CAPE) in the amelioration of inflammation and demyelination in the spinal cord of experimental autoimmune encephalomyelitis(EAE) mouse model multiple sclerosis, which could be a candidate therapy for MS. Multiple sclerosis is an autoimmune T-cell mediated disease, that T- cells become active, and differentiate into Th sub-set.α4β1integrin increased on the surface of T-cells during inflammation, which regulates immune cell cross through the blood-brain barrier into the central nervous system, and causes inflammation in the brain and spinal cord, myelin sheath damage, and neuron demyelination. The in-vivo experiment used mice. The twenty-five mice were divided into control negative, control positive, and three treatment groups. After this, EAE was induced in mice by injecting myelin oligodendrocyte glycoprotein peptide. The mice were monitored and scored daily for clinical signs. CAPE was orally administered to mice at 5 mg/kg for T1, 10 mg/kg for T2, and 20 mg/kg for T3 for 14 days. Immunofluorescence was used to assess α4integrin, Immunohistochemistry (IHC) was used to evaluate infiltration of CD3-T cell marker, and Luxol Fast Blue stain was used to evaluate demyelination. We found that CAPE treated mice model had a reduced infiltration of immune cells, demyelination in the spinal cord mice model, and decreasing α4integrin expression. These findings strongly demonstrated that CAPE could be a potential therapy for Multiple sclerosis, as it ameliorated the inflammation and demyelination in mice models.

Evaluating Therapeutic Plasma Exchange in Pediatric Acute Disseminated Encephalomyelitis: A Comprehensive Review.

Acute disseminated encephalomyelitis (ADEM) is a rare autoimmune disorder characterized by brain and spinal cord inflammation. In pediatric patients, ADEM presents unique challenges due to its potential for rapid progression and long-term neurological sequelae. Therapeutic plasma exchange (TPE) has emerged as a potential treatment option by targeting the underlying autoimmune process and modulating the inflammatory response. This comprehensive review evaluates the role of TPE in pediatric ADEM, synthesizing evidence from clinical studies and providing insights into its efficacy, safety, and potential benefits. The review highlights the variability in TPE efficacy based on disease severity and patient-specific factors. Implications for clinical practice include considering TPE as a therapeutic option, particularly in severe or refractory cases, and emphasizing the importance of early intervention. Recommendations for future research include long-term prospective studies, comparative effectiveness trials, and efforts to standardize TPE protocols. Overall, continued investigation and innovation in managing pediatric ADEM are essential for improving outcomes and quality of life for affected children and their families.

Dabrafenib mitigates the neuroinflammation caused by ferroptosis in experimental autoimmune encephalomyelitis by up regulating Axl receptor

Multiple sclerosis is an autoimmune disease that causes inflammatory damage to the central nervous system. At present, the pathogenesis of the disease is unknown. There is a lack of few effective therapy medications available. Therefore, it is necessary to further explore the pathogenesis of this illness and develop potential therapeutic drugs. Dabrafenib is potential therapeutic medicine for nervous system disease. In this study, we preliminarily studied the possible mechanism of dabrafenib in the treatment of multiple sclerosis from the perspective of ferroptosis. First, we observed that dabrafenib significantly improved symptoms of gait abnormalities, limb weakness or paralysis, and down-regulated levels of spinal cord inflammation in an experimental autoimmune encephalitis (EAE) model. Meanwhile, we also observed that dabrafenib could inhibit the proteins of ferroptosis in spinal cord tissue of EAE mice by Western blot. The results of immunohistochemical analysis showed that the effect of dabrafenib on ferroptosis mainly occurred in microglia. Second, dabrafenib was demonstrated to be able to inhibit the S phase of the cell cycle, reduce ROS levels, and reinstate mitochondrial activity in the LPS-induced BV2 inflammatory cell model. Futhermore, we found that dabrafenib inhibits P-JAK2 and P-STAT3 activation by acting Axl receptor, which in turn prevents neurogenic inflammation in microglia. The co-stimulated BV2 cell model with LPS and Erastin also verified these findings. Ultimately, the Axl knockout mice used to construct the EAE model allowed for the confirmation that dabrafenib prevented ferroptosis in microglia by up-regulating Axl receptor, which reduced the inflammatory demyelination associated with EAE. In summary, our research demonstrates the advantages of dabrafenib in multiple sclerosis treatment, which can prevent ferroptosis in microglia in multiple sclerosis through up-regulating Axl receptor, thus halting the progression of multiple sclerosis.

Effect of High Dose Methylprednisolone in Near Hanging Patients: A Retrospective Observational Study in a Tertiary Level Private Hospital in Bangladesh

Background: In the context of Bangladesh, hanging stands out as a notable method of suicide. This study focuses on patients who presented with near hanging, assessing their clinical profile, response to early management protocol and their outcome. Method: Spanning from January 1 to December 31, 2023, this retrospective study delves into the records of 10 Bangladeshi patients who engaged in near hanging. Demographic, clinical, and treatment particulars were collected along with initiation of early management protocol with an emphasis on the administration of high-dose methylprednisolone. The study evaluates the outcomes, including length of stay in the intensive care unit (ICU), and the need for intubation & mechanical ventilation, and in hospital mortality. Results: Within the specified sample size of 10 patients, comprising 30% men with a median age of 18 (range: 14–40), admission data revealed that 20% of patients had a Glasgow Coma Scale of ≤8, 10% exhibited hypotension, and no patient experienced hanging-induced cardiac arrest. All patients received high-dose methylprednisolone to reduce inflammation and oedema in injured spinal cord. Notably, a positive neurological outcome was observed in 90% of patients, with no reported mortality. The median length of stay in the ICU was 3 days, and only 10% of patients required intubation. Conclusion: The administration of high-dose methylprednisolone resulted in favourable outcomes. The study showed a zero-mortality rate, a median ICU stay of 3 days, and a 10% requirement for intubation. These findings emphasize the potential efficacy of high-dose methylprednisolone in managing near hanging cases in the Bangladeshi population, offering insights for future interventions and research. Bangladesh Crit Care J March 2024; 12 (1): 35-40

Long non-coding RNA DANCR increases spinal cord neuron apoptosis and inflammation of spinal cord injury by mediating the microRNA-146a-5p/MAPK6 axis.

This research was to unravel the impact of the lncRNA differentiation antagonizing non-protein coding RNA (DANCR)/microRNA (miR)-146a-5p/mitogen-activated protein kinase 6 (MAPK6) axis on spinal cord injury (SCI). SCI mouse models were established and injected with si-DANCR or miR-146a-5p agomir. The recovery of motor function was assessed by Basso Mouse Scale. SCI was pathologically evaluated, and serum inflammatory factors were measured in SCI mice. Mouse spinal cord neurons were injured by H2O2 and transfected, followed by assessment of proliferation and apoptosis. DANCR, miR-146a-5p, and MAPK6 in tissues and cells were detected, as well as their relationship. DANCR increased and miR-146a-5p decreased in SCI. Silencing DANCR or enhancing miR-146a-5p stimulated the proliferation of mouse spinal cord neurons and reduced apoptosis. DANCR was bound to miR-146a-5p to target MAPK6. DANCR affected the proliferation and apoptosis of spinal cord neurons by mediating the miR-146a-5p/MAPK6 axis. Downregulating DANCR or upregulating miR-146a-5p improved inflammation, the destruction of spinal cord tissue structure, and apoptosis in SCI mice. DANCR affects spinal cord neuron apoptosis and inflammation of SCI by mediating the miR-146a-5p/MAPK6 axis.

Combining imaging mass spectrometry and immunohistochemistry to analyse the lipidome of spinal cord inflammation

Inflammation is a complex process that accompanies many pathologies. Actually, dysregulation of the inflammatory process is behind many autoimmune diseases. Thus, treatment of such pathologies may benefit from in-depth knowledge of the metabolic changes associated with inflammation. Here, we developed a strategy to characterize the lipid fingerprint of inflammation in a mouse model of spinal cord injury. Using lipid imaging mass spectrometry (LIMS), we scanned spinal cord sections from nine animals injected with lysophosphatidylcholine, a chemical model of demyelination. The lesions were demonstrated to be highly heterogeneous, and therefore, comparison with immunofluorescence experiments carried out in the same section scanned by LIMS was required to accurately identify the morphology of the lesion. Following this protocol, three main areas were defined: the lesion core, the peri-lesion, which is the front of the lesion and is rich in infiltrating cells, and the uninvolved tissue. Segmentation of the LIMS experiments allowed us to isolate the lipid fingerprint of each area in a precise way, as demonstrated by the analysis using classification models. A clear difference in lipid signature was observed between the lesion front and the epicentre, where the damage was maximized. This study is a first step to unravel the changes in the lipidome associated with inflammation in the context of diverse pathologies, such as multiple sclerosis.Graphical abstract

Annulus Fibrosus Injury Induces Acute Neuroinflammation and Chronic Glial Response in Dorsal Root Ganglion and Spinal Cord-An In Vivo Rat Discogenic Pain Model.

Chronic painful intervertebral disc (IVD) degeneration (i.e., discogenic pain) is a major source of global disability needing improved knowledge on multiple-tissue interactions and how they progress in order improve treatment strategies. This study used an in vivo rat annulus fibrosus (AF) injury-driven discogenic pain model to investigate the acute and chronic changes in IVD degeneration and spinal inflammation, as well as sensitization, inflammation, and remodeling in dorsal root ganglion (DRG) and spinal cord (SC) dorsal horn. AF injury induced moderate IVD degeneration with acute and broad spinal inflammation that progressed to DRG to SC changes within days and weeks, respectively. Specifically, AF injury elevated macrophages in the spine (CD68) and DRGs (Iba1) that peaked at 3 days post-injury, and increased microglia (Iba1) in SC that peaked at 2 weeks post-injury. AF injury also triggered glial responses with elevated GFAP in DRGs and SC at least 8 weeks post-injury. Spinal CD68 and SC neuropeptide Substance P both remained elevated at 8 weeks, suggesting that slow and incomplete IVD healing provides a chronic source of inflammation with continued SC sensitization. We conclude that AF injury-driven IVD degeneration induces acute spinal, DRG, and SC inflammatory crosstalk with sustained glial responses in both DRGs and SC, leading to chronic SC sensitization and neural plasticity. The known association of these markers with neuropathic pain suggests that therapeutic strategies for discogenic pain need to target both spinal and nervous systems, with early strategies managing acute inflammatory processes, and late strategies targeting chronic IVD inflammation, SC sensitization, and remodeling.

Small extracellular vesicles from hypoxia-preconditioned bone marrow mesenchymal stem cells attenuate spinal cord injury via miR-146a-5p-mediated regulation of macrophage polarization.

JOURNAL/nrgr/04.03/01300535-202410000-00027/figure1/v/2024-02-06T055622Z/r/image-tiff Spinal cord injury is a disabling condition with limited treatment options. Multiple studies have provided evidence suggesting that small extracellular vesicles (SEVs) secreted by bone marrow mesenchymal stem cells (MSCs) help mediate the beneficial effects conferred by MSC transplantation following spinal cord injury. Strikingly, hypoxia-preconditioned bone marrow mesenchymal stem cell-derived SEVs (HSEVs) exhibit increased therapeutic potency. We thus explored the role of HSEVs in macrophage immune regulation after spinal cord injury in rats and their significance in spinal cord repair. SEVs or HSEVs were isolated from bone marrow MSC supernatants by density gradient ultracentrifugation. HSEV administration to rats via tail vein injection after spinal cord injury reduced the lesion area and attenuated spinal cord inflammation. HSEVs regulate macrophage polarization towards the M2 phenotype in vivo and in vitro. MicroRNA sequencing and bioinformatics analyses of SEVs and HSEVs revealed that miR-146a-5p is a potent mediator of macrophage polarization that targets interleukin-1 receptor-associated kinase 1. Reducing miR-146a-5p expression in HSEVs partially attenuated macrophage polarization. Our data suggest that HSEVs attenuate spinal cord inflammation and injury in rats by transporting miR-146a-5p, which alters macrophage polarization. This study provides new insights into the application of HSEVs as a therapeutic tool for spinal cord injury.

Formyl peptide receptor 2 regulates dendritic cell metabolism and Th17 cell differentiation during neuroinflammation.

Formyl peptide receptor 2 (FPR2) is a receptor for formylated peptides and specific pro-resolving mediators, and is involved in various inflammatory processes. Here, we aimed to elucidate the role of FPR2 in dendritic cell (DC) function and autoimmunity-related central nervous system (CNS) inflammation by using the experimental autoimmune encephalomyelitis (EAE) model. EAE induction was accompanied by increased Fpr2 mRNA expression in the spinal cord. FPR2-deficient (Fpr2 KO) mice displayed delayed onset of EAE compared to wild-type (WT) mice, associated with reduced frequencies of Th17 cells in the inflamed spinal cord at the early stage of the disease. However, FPR2 deficiency did not affect EAE severity after the disease reached its peak. FPR2 deficiency in mature DCs resulted in decreased expression of Th17 polarizing cytokines IL6, IL23p19, IL1β, and thereby diminished the DC-mediated activation of Th17 cell differentiation. LPS-activated FPR2-deficient DCs showed upregulated Nos2 expression and nitric oxide (NO) production, as well as reduced oxygen consumption rate and impaired mitochondrial function, including decreased mitochondrial superoxide levels, lower mitochondrial membrane potential and diminished expression of genes related to the tricarboxylic acid cycle and genes related to the electron transport chain, as compared to WT DCs. Treatment with a NO inhibitor reversed the reduced Th17 cell differentiation in the presence of FPR2-deficient DCs. Together, by regulating DC metabolism, FPR2 enhances the production of DC-derived Th17-polarizing cytokines and hence Th17 cell differentiation in the context of neuroinflammation.

Effects of oral and intranasal resveratrol nanoparticle administration on neurodegeneration and neuronal dysfunction in a model of multiple sclerosis

Aims/Purpose: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system. Immunomodulatory treatments seek to reduce inflammation in MS but have limited effect on neurodegeneration. Resveratrol is a natural polyphenol with antioxidant and anti‐inflammatory properties which could be neuroprotective in MS. The purpose of this study is to compare the oral and intranasal administration of resveratrol nanoparticles (RN) in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS with ocular and neurological endpoints.Methods: RN were formulated using a thin rehydration technique. In the 1st experiment, 16.9 mg/kg RN (n = 6) or equivalent vehicle (n = 5) were given orally to EAE mice daily for 30 days. In the 2nd experiment, 8.44 mg/kg RN (n = 6) or vehicle (n = 6) were given intranasally to EAE mice daily for 30 days. EAE mice were assessed daily for clinical signs of ascending paralysis and weekly for visual function. After sacrifice at day 30, retinas were immunostained for brn3a to count retinal ganglion cells (RGC), and spinal cords and optic nerves were stained by H&E and luxol fast blue to assess inflammation and demyelination.Results: 16.9 mg/kg oral RN treatment reduced RGC loss compared to vehicle (4164 ± 406 vs 2422 ± 401 RGC/1.56 mm2, p < 0.05). Similarly, 8.44 mg/kg RN given intranasally reduced RGC loss compared to vehicle (3569 ± 241 vs 2280 ± 329 RGC/1.56 mm2, p < 0.05). Oral and intranasal RN showed similar neuroprotective effects (4164 ± 406 vs 3569 ± 241 RGC/1.56 mm2, p > 0.05). Although neither route of administration showed a reduction of ascending paralysis, 16.9 mg/kg oral RN reduced the severity of paralysis compared to vehicle and 8.44 mg/kg intranasal RN (survival analysis with median survival 29.5 vs 19.0 and 19.0 days, p < 0.05). Likewise, the severity of visual function loss was reduced by the administration of 16.9 mg/kg oral RN compared to vehicle and 8.44 mg/kg intranasal RN (median survival > 28.0 vs 28.0 and 21.0 days, p < 0.05). Neither oral nor intranasal administration showed a significant reduction of spinal cord or optic nerve inflammation or demyelination.Conclusions: RN were able to reduce RGC loss independent of their administration route, but oral administration demonstrated additional neuroprotective effects by reducing paralysis severity.

Serum neurofilament and glial fibrillary acidic protein in idiopathic and seropositive transverse myelitis

BackgroundSerum levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) reflect the disease activity and disability in central nervous system (CNS) demyelinating diseases. However, the clinical significance of NfL and GFAP in idiopathic transverse myelitis (iTM), an inflammatory spinal cord disease with unknown underlying causes, remains unclear. This study aimed to investigate NfL and GFAP levels in iTM and their association with the clinical parameters compared with those in TM with disease-specific antibodies such as anti-aquaporin 4 or myelin oligodendrocyte glycoprotein antibodies (sTM). MethodsWe collected serum and clinical data of 365 patients with CNS inflammatory diseases from 12 hospitals. The serum NfL and GFAP levels were measured in patients with iTM (n = 37) and sTM (n = 39) using ultrasensitive single-molecule array assays. Regression analysis was performed to investigate the associations between serum levels of NfL and GFAP and the clinical parameters such as higher EDSS scores (EDSS ≥ 4.0). ResultsMean NfL levels were not significantly different between iTM (50.29 pg/ml) and sTM (63.18 pg/ml) (p = 0.824). GFAP levels were significantly lower in iTM (112.34 pg/ml) than in sTM (3814.20 pg/ml) (p = 0.006). NfL levels correlated with expanded disability status scale (EDSS) scores in sTM (p = 0.001) but not in iTM (p = 0.824). Disease duration also correlated with higher EDSS scores in sTM (p = 0.017). ConclusionNfL levels and disease duration correlated with EDSS scores in sTM, and GFAP levels could be a promising biomarker to differentiate iTM from sTM.

Expression of functionally distinct ecto-5'-nucleotidase/CD73 glycovariants in reactive astrocytes in experimental autoimmune encephalomyelitis and neuroinflammatory conditions in vitro.

Ecto-5'-nucleotidase/CD73 (eN/CD73) is a membrane-bound enzyme involved in extracellular production of adenosine and a cell adhesion molecule involved in cell-cell interactions. In neuroinflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), reactive astrocytes occupying active demyelination areas significantly upregulate eN/CD73 and express additional eN/CD73 variants. The present study investigated whether the different eN/CD73 variants represent distinct glycoforms and the functional consequences of their expression in neuroinflammatory states. The study was performed in animals at different stages of EAE and in primary astrocyte cultures treated with a range of inflammatory cytokines. Upregulation at the mRNA, protein, and functional levels, as well as the appearance of multiple eN/CD73 glycovariants were detected in the inflamed spinal cord tissue. At the peak of the disease, eN/CD73 exhibited higher AMP turnover and lower enzyme-substrate affinity than the control group, which was attributed to altered glycosylation under neuroinflammatory conditions. A subsequent in vitro study showed that primary astrocytes upregulated eN/CD73 and expressed the multiple glycovariants upon stimulation with TNFα, IL-1β, IL-6, and ATP, with the effect occurring at least in part via induction of JAK/STAT3 signaling. Experimental removal of glycan moieties from membrane glycoproteins by PNGaseF decreased eN/CD73 activity but had no effect on the enzyme's involvement in astrocyte migration. Our results suggest that neuroinflammatory states are associated with the appearance of functionally distinct eN/CD73 glycovariants, which may play a role in the development of the reactive astrocyte phenotype.

Carboplatin ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by inducing T cell apoptosis.

Apoptosis is a natural physiological process that can maintain the homeostasis of the body and immune system. This process plays an important role in the system's resistance to autoimmune development. Because of the dysfunction of cell apoptosis mechanism, the number of autoreactive cells in the peripheral tissue increases along with their accumulation. This will lead to the development of autoimmune diseases, such as multiple sclerosis (MS). MS is an immune-mediated disease of the central nervous system characterized by severe white matter demyelination. Because of the complexity of its pathogenesis, there is no drug to cure it completely. Experimental autoimmune encephalomyelitis (EAE) is an ideal animal model for the study of MS. Carboplatin (CA) is a second-generation platinum anti-tumor drug. In this study, we attempted to assess whether CA could be used to ameliorate EAE. CA reduced spinal cord inflammation, demyelination, and disease scores in mice with EAE. Moreover, the number and proportion of pathogenic T cells especially Th1 and Th17 in the spleen and draining lymph nodes were reduced in CA-treated EAE mice. Proteomic differential enrichment analysis showed that the proteins related to apoptosis signal changed significantly after CA treatment. CFSE experiment showed that CA significantly inhibited the T cell proliferation. Finally, CA also induced apoptosis in activated T cells and MOG-specific T cells in vitro. Overall, our findings indicated that CA plays a protective role in the initiation and progression of EAE and has the potential to be a novel drug in the treatment of MS.

Divergent functional outcomes of NLRP3 blockade downstream of multi-inflammasome activation: therapeutic implications for ALS.

NOD-Like Receptor Family Pyrin Domain Containing 3 (NLRP3) inflammasome modulation has emerged as a potential therapeutic approach targeting inflammation amplified by pyroptotic innate immune cell death. In diseases characterized by non-cell autonomous neurodegeneration including amyotrophic lateral sclerosis (ALS), the activation of several inflammasomes has been reported. Since functional redundancy can exist among inflammasome pathways, here we investigate the effects of NLRP3 inhibition on NLRP3, NLR family CARD Domain Containing 4 (NLRC4) and non-canonical pathways to understand whether NLRP3 blockade alone can mitigate pro-inflammatory cytokine release and pyroptotic cell death in contexts where single or multiple inflammasome pathways independent of NLRP3 are activated. In this study we do not limit our insights into inflammasome biology by solely relying on the THP-1 monocytic line under the LPS/nigericin-mediated NLRP3 pathway activation paradigm. We assess therapeutic potential and limitations of NLRP3 inhibition in multi-inflammasome activation contexts utilizing various human cellular systems including cell lines expressing gain of function (GoF) mutations for several inflammasomes, primary human monocytes, macrophages, healthy and Amyotrophic Lateral Sclerosis (ALS) patient induced pluripotent stem cells (iPSC)-derived microglia (iMGL) stimulated for canonical and non-canonical inflammasome pathways. We demonstrate that NLRP3 inhibition can modulate the NLRC4 and non-canonical inflammasome pathways; however, these effects differ between immortalized, human primary innate immune cells, and iMGL. We extend our investigation in more complex systems characterized by activation of multiple inflammasomes such as the SOD1G93A mouse model. Through deep immune phenotyping by single-cell mass cytometry we demonstrate that acute NLRP3 inhibition does not ameliorate spinal cord inflammation in this model. Taken together, our data suggests that NLRP3 inhibition alone may not be sufficient to address dynamic and complex neuroinflammatory pathobiological mechanisms including dysregulation of multiple inflammasome pathways in neurodegenerative disease such as ALS.

Minimally Invasive Microglial and Neuronal Imaging in Mouse Spinal Cord Dorsal Horn

The spinal cord dorsal horn is a relay hub that receives sensory information from the peripheral nervous system and transmits bioelectrical signals to the brain. <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">In vivo</i> imaging of neuronal and glial activity in the dorsal horn can provide insights into both functions and dysfunctions of the neuronal network in the spinal cord. With multimodal NLO microscopy, we identified a thin-myelin sheath region allowing to image over 200 μm deep below pia with subcellular resolution. By using an optically cleared intervertebral window, dorsal horn neuron and microglia activities can be observed without activating spinal cord inflammation. Two-photon imaging of neurons and microglia as well as the optical clearing improvement at different tissue depths were further characterized over time. Using this inflammation-free imaging method, we conducted a longitudinal study of dorsal horn microglia dynamics following sciatic nerve transection. Furthermore, stable <italic xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">in vivo</i> calcium imaging of neurons in the dorsal horn was performed with electrical stimulation on the mouse's hind paw. The subcellular-resolution imaging enabled characterization of the distinct calcium transients of neuronal somas and dendrites. This minimally invasive imaging approach to spinal dorsal horn through an optically cleared intervertebral window provides a reliable platform for studying and understanding cellular activities in the spinal dorsal horn.

Transverse Myelitis Caused by Spinal Dural Arteriovenous Fistula: A Case Report

Spinal cord pathology is a diverse topic with a broad range of causes. Etiologies include trauma, inflammatory processes, infections, vascular disease, neoplasm, degenerative conditions and toxin exposure. Regardless of etiology, spinal pathology often presents as rapidly progressive paraparesis. Transverse Myelitis (TM) is a rare, acute segmental inflammatory spinal cord disorder characterized with motor, sensory, and/or autonomic dysfunction. This process usually occurs post-infection, but may also be related to acute neuro-inflammatory disorders. This paper will present a case of TM refractory to medication and describe the diagnosis of Spinal Dural Arteriovenous Fistula (SDAVF). SDAVF is a rare condition in which there is an arteriovenous fistula formed on the dural surface of the spinal cord which typically drains via retrograde flow through the medullary vein, thereby causing enlargement of coronal venous plexus.

Sciatic Nerve Block Combined with Flurbiprofen Inhibits Spinal Cord Inflammation and Improves Postoperative Pain in Rats with Plantar Incision.

Peripheral nerve block is often used to relieve postoperative pain. But the effect of nerve block on inflammatory response is not fully understood. Spinal cord is the primary center of pain processing. This study is to investigate the effect of single sciatic nerve block on the inflammatory response of the spinal cord in rats with plantar incision and the combined effect with flurbiprofen. The plantar incision was used to establish a postoperative pain model. Single sciatic nerve block, intravenous flurbiprofen or the combination of both were used for intervention. The sensory and motor functions after nerve block and incision were evaluated. The changes of IL-1β, IL-6, TNF-α, microglia and astrocytes in the spinal cord were examined by qPCR and immunofluorescence respectively. Sciatic nerve block with 0.5% ropivacaine in rats induced sensory block for 2h and motor block for 1.5h. In the rats with plantar incision, the single sciatic nerve block did not alleviate postoperative pain or inhibit the activation of spinal microglia and astrocytes, but the levels of IL-1β and IL-6 in spinal cord were decreased when the nerve block wore off. The combined effect of a single sciatic nerve block and intravenous flurbiprofen not only decreased the levels of IL-1β, IL-6, and TNF-α, but also relieved the pain and alleviated the activation of microglia and astrocytes. The single sciatic nerve block cannot improve postoperative pain or inhibit the activation of spinal cord glial cells, but can reduce the expression of spinal inflammatory factors. Nerve block combined with flurbiprofen can inhibit spinal cord inflammation and improve postoperative pain. This study provides a reference for rational clinical application of nerve block.