The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation

AbstractSpinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA2 and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA2 activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro, we utilized bone marrow-derived macrophages to determine myelin’s effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS + INF-γ; M1) macrophage activation, whereas myelin did not induce pro-inflammatory responses in unstimulated or anti-inflammatory (IL-4; M2) macrophages. Specifically, myelin increased levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide production in M1 macrophages as well as M1-mediated neurotoxicity. PACOCF3 (cPLA2 inhibitor) blocked myelin’s detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA2 play an important role in the pathophysiology of SCI inflammation and the phenotype-specific response to myelin implicate diverse roles of myelin in neuroinflammatory conditions.

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Therapeutic Effects of Azithromycin on Spinal Cord Injury in Male Wistar Rats: A Role for Inflammatory Pathways

Journal of Neurological Surgery Part A Central European Neurosurgery ◽

10.1055/s-0041-1735854 ◽

2021 ◽

Author(s):

Ali Rismanbaf ◽

Khashayar Afshari ◽

Mehdi Ghasemi ◽

Abolfazl Badripour ◽

Arvin Haj-Mirzaian ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Wistar Rats ◽

Inflammatory Responses ◽

Macrophage Polarization ◽

M2 Macrophage ◽

Therapeutic Effects ◽

Spinal Cord Tissue ◽

Cord Injury ◽

Male Wistar Rats

Abstract Background Inflammatory responses, including macrophages/microglia imbalance, are associated with spinal cord injury (SCI) complications. Accumulating evidence also suggests an anti-inflammatory property of azithromycin (AZM). Material and Methods Male Wistar rats were subjected to T9 vertebra laminectomy. SCI was induced by spinal cord compression at this level with an aneurysmal clip for 60 seconds. They were divided into three groups: the sham-operated group and two SCI treatment (normal saline as a vehicle control vs. AZM at 180 mg/kg/d intraperitoneally for 3 days postsurgery; first dose: 30 minutes after surgery) groups. Locomotor scaling and behavioral tests for neuropathic pain were evaluated and compared through a 28-day period. At the end of the study, tissue samples were taken to assess neuroinflammatory changes and neural demyelination using ELISA and histopathologic examinations, respectively. In addition, the proportion of M1/M2 macrophage polarization was assessed by using flow cytometry. Results Post-SCI AZM treatment (180 mg/kg/d for 3 days) significantly improved locomotion (p < 0.01) and decreased sensitivity to mechanical (p < 0.01) and thermal allodynia (p < 0.001). Moreover, there was a significant tumor necrosis factor-α (TNF-α) decline (p < 0.01) and interleukin-10 (IL-10) elevation (p < 0.01) in the spinal cord tissue of the AZM-treated group compared with the control groups 28 days post-SCI. AZM significantly improved neuroinflammation as evidenced by reduction of the M1 expression, elevation of M2 macrophages, and reduction of the M1/M2 ratio in both the dorsal root ganglion and the spinal cord tissue after SCI compared with controls (p < 0.01). Conclusion AZM treatment can be considered a therapeutic agent for SCI, as it could reduce neuroinflammation and SCI sensory/locomotor complications.

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The Repression of the HMGB1-TLR4-NF-κB Signaling Pathway by Safflower Yellow May Improve Spinal Cord Injury

Frontiers in Neuroscience ◽

10.3389/fnins.2021.803885 ◽

2021 ◽

Vol 15 ◽

Author(s):

Lu Wang ◽

Benson O. A. Botchway ◽

Xuehong Liu

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Signaling Pathway ◽

Nuclear Translocation ◽

Inflammatory Responses ◽

Nerve Tissue ◽

Inflammatory Factors ◽

Spinal Cord Tissue ◽

Pathophysiological Mechanism ◽

Cord Injury

Spinal cord injury (SCI) often results in abnormal sensory and motor functions. Current interventions for SCI in the clinical setting are not effective partly due to the complexity concerning its pathophysiological mechanism. In the wake of SCI, considerable inflammatory cells assemble around the injured area that induces a series of inflammatory reactions and aggravates tissue lesions, thereby affecting the recovery of the damaged nerve tissue. Therefore, the inhibition of inflammatory responses can improve the repair of the injured spinal cord tissue. Safflower Yellow (SY) is the main active ingredient of Carthamus tinctorius. SY has anti-inflammatory effect, as it can inhibit IκBα phosphorylation to impede the NF-κB signaling pathway and p53 nuclear translocation. Besides, SY can limit the release of pro-inflammatory factors, which in turn may alleviate secondary SCI and prevent further complications. In this report, we analyze the pathophysiological mechanism of SCI, the role of inflammatory responses, and how SY interferes with the HMGB1-TLR-4-NF-κB signaling pathway to attenuate inflammatory responses in SCI.

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Antithrombin reduces the ischemia/reperfusion-induced spinal cord injury in rats by attenuating inflammatory responses

Thrombosis and Haemostasis ◽

10.1160/th03-06-0385 ◽

2004 ◽

Vol 91 (01) ◽

pp. 162-170 ◽

Cited By ~ 22

Author(s):

Koji Hirose ◽

Yuji Taoka ◽

Mitsuhiro Uchiba ◽

Kan-yu Nakano ◽

Junichi Utoh ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Motor Neurons ◽

Inflammatory Responses ◽

Ischemia Reperfusion ◽

Spinal Cord Tissue ◽

Protective Effects ◽

Tissue Levels ◽

Cord Injury

SummaryAntithrombin (AT) reveals its antiinflammatory activity by promoting endothelial release of prostacyclin (PGI2) in vivo. Since neuroinflammation is critically involved in the development of ischemia/reperfusion (I/R)-induced spinal cord injury (SCI), it is possible that AT reduces the I/R-induced SCI by attenuating the inflammatory responses. We examined this possibility using rat model of I/R-induced SCI in the present study. AT significantly reduced the mortality and motor disturbances by inhibiting reduction of the number of motor neurons in animals subjected to SCI. Microinfarctions of the spinal cord seen after reperfusion were markedly reduced by AT. AT significantly enhanced the I/R-induced increases in spinal cord tissue levels of 6-keto-PGF1α, a stable metabolite of PGI2. AT significantly inhibited the I/R-induced increases in spinal cord tissue levels of TNF-α, rat interleukin-8 and myeloperoxidase. In contrast,Trp49-modified AT did not show any protective effects. Pretreatment with indomethacin significantly reversed the protective effects of AT.An inactive derivative of factor Xa, which selectively inhibits thrombin generation, has been shown to fail to reduce SCI.Taken together, these observations strongly suggested that AT might reduce I/R-induced SCI mainly by the antiinflammatory effect through promotion of endothelial production of PGI2. These findings also suggested that AT might be a potential neuroprotective agent.

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Spinal Cord Tissue Bridges Validation Study: Predictive Relationships With Sensory Scores Following Cervical Spinal Cord Injury

Topics in Spinal Cord Injury Rehabilitation ◽

10.46292/sci21-00018 ◽

2021 ◽

Author(s):

Andrew C. Smith ◽

Denise R. O’Dell ◽

Wesley A. Thornton ◽

David Dungan ◽

Eli Robinson ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

External Validation ◽

Inpatient Rehabilitation ◽

Spinal Cord Tissue ◽

Light Touch ◽

Post Injury ◽

Data Set ◽

Cord Injury ◽

Predictive Relationships

Background: Using magnetic resonance imaging (MRI), widths of ventral tissue bridges demonstrated significant predictive relationships with future pinprick sensory scores, and widths of dorsal tissue bridges demonstrated significant predictive relationships with future light touch sensory scores, following spinal cord injury (SCI). These studies involved smaller participant numbers, and external validation of their findings is warranted. Objectives: The purpose of this study was to validate these previous findings using a larger independent data set. Methods: Widths of ventral and dorsal tissue bridges were quantified using MRI in persons post cervical level SCI (average 3.7 weeks post injury), and pinprick and light touch sensory scores were acquired at discharge from inpatient rehabilitation (average 14.3 weeks post injury). Pearson product-moments were calculated and linear regression models were created from these data. Results: Wider ventral tissue bridges were significantly correlated with pinprick scores (r = 0.31, p < 0.001, N = 136) and wider dorsal tissue bridges were significantly correlated with light touch scores (r = 0.31, p < 0.001, N = 136) at discharge from inpatient rehabilitation. Conclusion: This retrospective study’s results provide external validation of previous findings, using a larger sample size. Following SCI, ventral tissue bridges hold significant predictive relationships with future pinprick sensory scores and dorsal tissue bridges hold significant predictive relationships with future light touch sensory scores.

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Transplantation of Mesenchymal Stem Cells Promotes an Alternative Pathway of Macrophage Activation and Functional Recovery after Spinal Cord Injury

Journal of Neurotrauma ◽

10.1089/neu.2011.2109 ◽

2012 ◽

Vol 29 (8) ◽

pp. 1614-1625 ◽

Cited By ~ 220

Author(s):

Hideaki Nakajima ◽

Kenzo Uchida ◽

Alexander Rodriguez Guerrero ◽

Shuji Watanabe ◽

Daisuke Sugita ◽

...

Keyword(s):

Spinal Cord ◽

Stem Cells ◽

Spinal Cord Injury ◽

Mesenchymal Stem Cells ◽

Functional Recovery ◽

Macrophage Activation ◽

Alternative Pathway ◽

Cord Injury

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The human ApoE4 variant reduces functional recovery and neuronal sprouting after incomplete spinal cord injury in male mice

10.1101/2020.11.05.369900 ◽

2020 ◽

Author(s):

Carlos A. Toro ◽

Jens Hansen ◽

Mustafa M. Siddiq ◽

Kaitlin Johnson ◽

Wei Zhao ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Inflammatory Responses ◽

Synaptic Activity ◽

Cord Injury ◽

Hospital Stays ◽

Human Apoe3 ◽

Neuronal Sprouting ◽

Apoe Genotypes ◽

Upregulated Genes

AbstractSpinal cord injury (SCI) is a devastating form of neurotrauma. Patients who carry one or two ApoE4 alleles show worse functional outcomes and longer hospital stays after SCI but the cellular and molecular underpinnings for this genetic link remain poorly understood. Thus, there is a great need to generate animal models to accurately replicate the genetic determinants of outcomes after SCI to spur development of treatments that improve physical function. Here, we examined outcomes after a moderate contusion SCI of transgenic mice expressing human ApoE3 or ApoE4. ApoE4 mice have worse locomotor function and coordination after SCI. Histological examination revealed greater glial staining in ApoE4 mice after SCI associated with reduced levels of neuronal sprouting markers. Bulk RNA sequencing revealed that subcellular processes (SCPs), such as extracellular matrix organization and inflammatory responses, were highly-ranked among upregulated genes at 7 days after SCI in ApoE4 variants. Conversely, SCPs related to neuronal action potential and neuron projection development were increased in ApoE3 mice at 21 days. In summary, our results reveal a clinically relevant SCI mouse model that recapitulates the influence of ApoE genotypes on post-SCI function in individuals who carry these alleles and suggest that the mechanisms underlying worse recovery for ApoE4 animals involve glial activation and loss of sprouting and synaptic activity.

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METHODS OF PHYSIOTHERAPY FOR STUDY IN A SPINAL INSULT

Knowledge International Journal ◽

10.35120/kij29082565d ◽

2018 ◽

Vol 28 (7) ◽

pp. 2565-2566

Author(s):

Daniela Popova ◽

Mariela Filipova

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Back Pain ◽

Young People ◽

Hemorrhagic Stroke ◽

Muscle Spasm ◽

Spinal Cord Tissue ◽

Blood Diseases ◽

Cord Injury ◽

Ischemic Spinal Cord Injury

Spinal stroke is a disease that is rare in neurological practice. Affects young people, mostly at the age of 30 years [2]. It may be ischemic or haemorrhagic. Etiological, ischemic spinal stroke is caused by atherosclerosis of the aorta and blood vessels of the spinal cord, muscle spasm, vasculitis, pregnancy, hemangioma or hernia [3, 4]. Hemorrhagic stroke is caused by dysplasia, tumors and blood diseases involving increased bleeding [1]. Spinal infarction most commonly develops in the basal spinal artery pool, which is responsible for the blood supply of the anterior 2/3 of the spinal cord tissue. Often, the disease starts with a sudden back pain with an enigmatic nature (in the area of the thoracic segment - Th 8), a gradually occurring weakness in the limbs and hypestesia, pelvic-tangle disorders [5]. The gait is very difficult to impossible.Purpose of the study: To test neurological tests in patients with spinal ischemic spinal cord injury. Assess their accessibility and reliability.

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Inhibition of x-irradiation–enhanced locomotor recovery after spinal cord injury by hyperbaric oxygen or the antioxidant nitroxide tempol

Journal of Neurosurgery Spine ◽

10.3171/spi.2007.6.4.9 ◽

2007 ◽

Vol 6 (4) ◽

pp. 337-343 ◽

Cited By ~ 7

Author(s):

Virany H. Hillard ◽

Hong Peng ◽

Kaushik Das ◽

Raj Murali ◽

Chitti R. Moorthy ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Hyperbaric Oxygen ◽

Spinal Cord Tissue ◽

Irradiation Site ◽

Injury Site ◽

Locomotor Recovery ◽

Locomotor Function ◽

Cord Injury ◽

X Irradiation

Object Hyperbaric oxygen (HBO), the nitroxide antioxidant tempol, and x-irradiation have been used to promote locomotor recovery in experimental models of spinal cord injury. The authors used x-irradiation of the injury site together with either HBO or tempol to determine whether combined therapy offers greater benefit to rats. Methods Contusion injury was produced with a weight-drop device in rats at the T-10 level, and recovery was determined using the 21-point Basso-Beattie-Bresnahan (BBB) locomotor scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater after x-irradiation (20 Gy) of the injury site or treatment with tempol (275 mg/kg intraperitoneally) than in untreated rats (final BBB Scores 10.6 [x-irradiation treated] and 9.1 [tempol treated] compared with 6.4 [untreated], p < 0.05). Recovery was not significantly improved by HBO (2 atm for 1 hour [BBB Score 8.2, p > 0.05]). Interestingly, the improved recovery of locomotor function after x-irradiation, in contrast with antiproliferative radiotherapy for neoplasia, was inhibited when used together with either HBO or tempol (BBB Scores 8.2 and 8.3, respectively). The ability of tempol to block enhanced locomotor recovery by x-irradiation was accompanied by prevention of alopecia at the irradiation site. The extent of locomotor recovery following treatment with tempol, HBO, and x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter. Conclusions These results suggest that these treatments, when used alone, can activate neuroprotective mechanisms but, in combination, may result in neurotoxicity.

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