scholarly journals Neuroprotective Effect of Subdural Infusion of Serp-1 in Spinal Cord Trauma

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 372 ◽  
Author(s):  
Jacek M. Kwiecien ◽  
Wojciech Dabrowski ◽  
Bryce J. Kwiecien-Delaney ◽  
Christian J. Kwiecien-Delaney ◽  
Dorota Siwicka-Gieroba ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Neuroprotective Effect ◽  
Optimal Dose ◽  
Myxoma Virus ◽  
Macrophage Infiltration ◽  
Inflammatory Damage ◽  
Cord Injury ◽  
Destructive Inflammation ◽  
Inflammatory Macrophages ◽  
Inflammatory Effect

Spinal cord injury (SCI) initiates a severe, destructive inflammation with pro-inflammatory, CD68+/CD163−, phagocytic macrophages infiltrating the area of necrosis and hemorrhage by day 3 and persisting for the next 16 weeks. Inhibition of macrophage infiltration of the site of necrosis that is converted into a cavity of injury (COI) during the first week post-SCI, should limit inflammatory damage, shorten its duration and result in neuroprotection. By sustained subdural infusion we administered Serp-1, a Myxoma virus-derived immunomodulatory protein previously shown to improve neurologic deficits and inhibit macrophage infiltration in the COI in rats with the balloon crush SCI. Firstly, in a 7 day long study, we determined that the optimal dose for macrophage inhibition was 0.2 mg/week. Then, we demonstrated that a continuous subdural infusion of Serp-1 for 8 weeks resulted in consistently accelerated lowering of pro-inflammatory macrophages in the COI and in their almost complete elimination similar to that previously observed at 16 weeks in untreated SCI rats. The macrophage count in the COI is a quantitative test directly related to the severity of destructive inflammation initiated by the SCI. This test has consistently demonstrated anti-inflammatory effect of Serp-1 interpreted as neuroprotection, the first and necessary step in a therapeutic strategy in neurotrauma.

Neuroprotective Effect of Epidural Electrical Stimulation against Ischemic Spinal Cord Injury in Rats

2005 ◽  
Vol 103 (1) ◽  
pp. 84-92 ◽  
Author(s):  
Manabu Kakinohana ◽  
Hideki Harada ◽  
Yasunori Mishima ◽  
Tatsuhiko Kano ◽  
Kazuhiro Sugahara
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Electrical Stimulation ◽  
Neuroprotective Effect ◽  
Spinal Cord Ischemia ◽  
Aortic Occlusion ◽  
Cord Injury ◽  
Optimal Setting ◽  
Transient Aortic Occlusion ◽  
Ischemic Spinal Cord Injury

Background Electroconvulsion therapy is likely to serve as an effective preconditioning stimulus for inducing tolerance to ischemic brain injury. The current study examines whether electrical stimuli on the spinal cord is also capable of inducing tolerance to ischemic spinal cord injury by transient aortic occlusion. Methods Spinal cord ischemia was induced by occlusion of the descending thoracic aorta in combination with maintaining systemic hypotension (40 mmHg) during the procedure. Animals implanted with epidural electrodes were divided into four groups according to electrical stimulation and sham. Two groups consisted of rapid preconditioning (RE group, n = 8) and sham procedure (RC group, n = 8) 30 min before 9 min of spinal cord ischemia. In the two groups that underwent delayed preconditioning, rats were exposed to 9 min of aortic occlusion 24 h after either pretreatment with epidural electrical stimulation (DE group, n = 8) or sham (DC group, n = 8). In addition, rats were exposed to 6-11 min of spinal cord ischemia at 30 min or 24 h after epidural electrical stimulation or sham stimulation. The group P50 represents the duration of spinal cord ischemia associated with 50% probability of resultant paraplegia. Results Pretreatment with electrical stimulation in the DE group but not the RE group protected the spinal cord against ischemia, and this stimulation prolonged the P50 by approximately 15.0% in the DE group compared with the DC group. Conclusions Although the optimal setting for this electrical preconditioning should be determined in future studies, the results suggest that epidural electrical stimulation will be a useful approach to provide spinal protection against ischemia.

Neuroprotective Effect of Vaccination with Autoantigen-Pulsed Dendritic Cells After Spinal Cord Injury

2012 ◽  
Vol 176 (1) ◽  
pp. 281-292 ◽  
Author(s):  
Yufu Wang ◽  
Ke Wang ◽  
Rui Chao ◽  
Jing Li ◽  
Lei Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Dendritic Cells ◽  
Neuroprotective Effect ◽  
Cord Injury

Neuroprotective Effect of Endogenous Pituitary Adenylate Cyclase-Activating Polypeptide on Spinal Cord Injury

2012 ◽  
Vol 48 (3) ◽  
pp. 508-517 ◽  
Author(s):  
Daisuke Tsuchikawa ◽  
Tomoya Nakamachi ◽  
Masashi Tsuchida ◽  
Yoshihiro Wada ◽  
Motohide Hori ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Adenylate Cyclase ◽  
Neuroprotective Effect ◽  
Cord Injury ◽  
Pituitary Adenylate Cyclase

Exosome derived from mesenchymal stem cells enhance autophagy and inhibit iNOS/TXNIP/NLRP3 inflammasome axis in injured spinal cord

2020 ◽  
Author(s):  
Bin Lv ◽  
Lei Wang ◽  
Anquan Huang ◽  
Tianming Zou ◽  
Jishan Yuan
Keyword(s):  
Nitric Oxide ◽  
Spinal Cord ◽  
Nlrp3 Inflammasome ◽  
Neuroprotective Effect ◽  
Neuronal Cells ◽  
Tissue Loss ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Cord Injury

Abstract Background: Neuroinflammation, autophagy, NLRP3 inflammasome, and microglia polarizationhave been implicated in spinal cord injury (SCI).Moreover, exosomes, a classic nanovesicles secreted by MSCs, may have a neuroprotective effect on transformation of microglia from the M1 state to the M2 phenotype. However, the effect of MSCs derived exosomes on neuroinflammation is still unclear. Here, we investigated the mechanisms of MSCs derived exosomes mediated NLRP3 inflammasome signaling cascades and its protective effects in SCI. Methods:The SCI model was performed by weight-drop impact in adult male Sprague-Dawley (SD) rats. Control andexosome rats were randomly subjecttoexosomeadminister (20 mg/kg) or placebo via intraperitoneal route 1 h after SCI.Autophagy inhibitor(3-MA) was administered intraperitoneally 20 min before experiment.Neurological function was measured by Basso-Beattie-Bresnahan (BBB) scoring and an open-field test.Neuronal death was measured by HE stainingandNisslstaining.Inducible nitric oxide synthase (iNOS) levels were determined using fluorescent probes. The autophagy and TXNIP and its downstream signaling pathways-mediated polarization of macrophages/microglia was assessed by immunohistochemistry. Results:Exosome significantly downregulated intracellular iNOS and inhibited TXNIP, pyrin domain-containing 3 (NLRP3) inflammasome pathway activation by activating autophagy. Additionally, Exosomepromoted expression of autophagy markers, such as LC3A/B and beclin1,and abrogated the expression of p62. Autophagy inhibitor, 3-MA, blockage of autophagy flux abolished the inhibition of apoptosis and iNOS/TXNIP/NLRP3 inflammasome axisafterSCI. Here, we demonstrated that exosomeadministration in spinal cord markedly reduced tissue loss, attenuate pathological morphology of the injuredregion, and promoted tissue recovery. Moreover. our resultshowed that exosome administration alleviated neuronal cells apoptosis, and inhibited nitric oxide release in microglia.The activation of inflammatoryresponse in neuronal cells facilitates interactions of iNOS‐NLRP3 andTXNIP‐NLRP3and inhibited NLRP3 inflammasome where neuronal cells apoptosis was induced.Further, we found that exosome could suppress macrophages/microglia polarized to M1 phenotype in vivo and in vitro.Taken together, exosome administration exerts protective effects in neuronal cells through inhibiting iNOS production, and exosome administration could inhibit iNOS/TXNIP/NLRP3 inflammasome axis via enhancing autophagy and both in vitro and in vivo. Conclusions:These resultsreveal that exosometreatment alleviatedneuroinflammation and mitigates neuronal apoptosis via autophagy-mediate inhibition of the iNOS/TXNIP/NLRP3 inflammasome axis. Our findings suggest that exosome may be a novel therapeutic target for treating SCI.

scholarly journals Inhibiting HMGB1-RAGE axis prevents pro-inflammatory macrophages/microglia polarization and affords neuroprotection after spinal cord injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Hong Fan ◽  
Hai-Bin Tang ◽  
Zhe Chen ◽  
Hu-Qing Wang ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Western Blot ◽  
Functional Recovery ◽  
Sterile Inflammation ◽  
Qrt Pcr ◽  
Cord Injury ◽  
Microglia Polarization ◽  
Anti Inflammatory ◽  
Inflammatory Macrophages

Abstract Background Spinal cord injury (SCI) favors a persistent pro-inflammatory macrophages/microglia-mediated response with only a transient appearance of anti-inflammatory phenotype of immune cells. However, the mechanisms controlling this special sterile inflammation after SCI are still not fully elucidated. It is known that damage-associated molecular patterns (DAMPs) released from necrotic cells after injury can trigger severe inflammation. High mobility group box 1(HMGB1), a ubiquitously expressed DNA binding protein, is an identified DAMP, and our previous study demonstrated that reactive astrocytes could undergo necroptosis and release HMGB1 after SCI in mice. The present study aimed to explore the effects and the possible mechanism of HMGB1on macrophages/microglia polarization, as well as the neuroprotective effects by HMGB1 inhibition after SCI. Methods In this study, the expression and the concentration of HMGB1 was determined by qRT-PCR, ELISA, and immunohistochemistry. Glycyrrhizin was applied to inhibit HMGB1, while FPS-ZM1 to suppress receptor for advanced glycation end products (RAGE). The polarization of macrophages/microglia in vitro and in vivo was detected by qRT-PCR, immunostaining, and western blot. The lesion area was detected by GFAP staining, while neuronal survival was examined by Nissl staining. Luxol fast blue (LFB) staining, DAB staining, and western blot were adopted to evaluate the myelin loss. Basso-Beattie-Bresnahan (BBB) scoring and rump-height Index (RHI) assay was applied to evaluate locomotor functional recovery. Results Our data showed that HMGB1 can be elevated and released from necroptotic astrocytes and HMGB1 could induce pro-inflammatory microglia through the RAGE-nuclear factor-kappa B (NF-κB) pathway. We further demonstrated that inhibiting HMGB1 or RAGE effectively decreased the numbers of detrimental pro-inflammatory macrophages/microglia while increased anti-inflammatory cells after SCI. Furthermore, our data showed that inhibiting HMGB1 or RAGE significantly decreased neuronal loss and demyelination, and improved functional recovery after SCI. Conclusions The data implicated that HMGB1-RAGE axis contributed to the dominant pro-inflammatory macrophages/microglia-mediated pro-inflammatory response, and inhibiting this pathway afforded neuroprotection for SCI. Thus, therapies designed to modulate immune microenvironment based on this cascade might be a prospective treatment for SCI.

Downregulation of Long Noncoding RNA TUG1 Attenuates MTDH-Mediated Inflammatory Damage via Targeting miR-29b-1-5p After Spinal Cord Ischemia Reperfusion

2020 ◽  
Author(s):  
Hui Jia ◽  
Zhe Li ◽  
Yi Chang ◽  
Bo Fang ◽  
Yongjian Zhou ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Noncoding Rna ◽  
Target Genes ◽  
Neuroprotective Effect ◽  
Ischemia Reperfusion ◽  
Spinal Cord Ischemia ◽  
Specific Inhibitor ◽  
Direct Interaction ◽  
Luciferase Reporter ◽  
Inflammatory Damage

Abstract Long noncoding RNAs and microRNAs (miRNAs) play a vital role in spinal cord ischemia reperfusion (IR) injury. The aim of this study was to identify the potential interactions between taurine upregulated gene 1 (TUG1) and miRNA-29b-1-5p in a rat model of spinal cord IR. The IR injury was established by 14-minute occlusion of aortic arch. TUG1 and metadherin (MTDH) knockdown were induced by respective siRNAs, and miR-29b-1-5p expression was modulated using specific inhibitor or mimics. The interactions between TUG1, miR-29b-1-5p, and the target genes were determined using the dual-luciferase reporter assay. We found that IR respectively downregulated and upregulated miR-29b-1-5p and TUG1, and significantly increased MTDH expression. MTDH was predicted as a target of miR-29b-1-5p and its knockdown downregulated NF-κB and IL-1β levels. A direct interaction was observed between TUG1 and miR-29b-1-5p, and knocking down TUG1 upregulated the latter. Furthermore, overexpression of miR-29b-1-5p or knockdown of TUG1 alleviated blood-spinal cord barrier leakage and improved hind-limb motor function by suppressing MTDH and its downstream pro-inflammatory cytokines. Knocking down TUG1 also alleviated MTDH/NF-κB/IL-1β pathway-mediated inflammatory damage after IR by targeting miR-29b-1-5p, whereas blocking the latter reversed the neuroprotective effect of TUG1 knockdown and restored MTDH/NF-κB/IL-1β levels.

scholarly journals Tamoxifen Promotes Axonal Preservation and Gait Locomotion Recovery after Spinal Cord Injury in Cats

2016 ◽  
Vol 2016 ◽  
pp. 1-16 ◽  
Author(s):  
Braniff de la Torre Valdovinos ◽  
Judith Marcela Duenas Jimenez ◽  
Ismael Jimenez Estrada ◽  
Jacinto Banuelos Pineda ◽  
Nancy Elizabeth Franco Rodriguez ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Normal Values ◽  
Angular Displacement ◽  
Neuroprotective Effect ◽  
Ventral Horn ◽  
Tamoxifen Treatment ◽  
Myelinated Axons ◽  
Cord Injury ◽  
Hindlimb Kinematics

We performed experiments in cats with a spinal cord penetrating hemisection at T13-L1 level, with and without tamoxifen treatment. The results showed that the numbers of the ipsilateral and contralateral ventral horn neurons were reduced to less than half in the nontreated animals compared with the treated ones. Also, axons myelin sheet was preserved to almost normal values in treated cats. On the contrary, in the untreated animals, their myelin sheet was reduced to 28% at 30 days after injury (DAI), in both the ipsilateral and contralateral regions of the spinal cord. Additionally, we made hindlimb kinematics experiments to study the effects of tamoxifen on cat locomotion after the injury: at 4, 16, and 30 DAI. We observed that the ipsilateral hindlimb angular displacement (AD) of the pendulum-like movements (PLM) during gait locomotion was recovered to almost normal values in treated cats. Contralateral PLM acquired similar values to those obtained in intact cats. At 4 DAI, untreated animals showed a compensatory increment of PLM occurring in the contralateral hindlimb, which was partially recovered at 30 DAI. Our findings indicate that tamoxifen exerts a neuroprotective effect and preserves or produces myelinated axons, which could benefit the locomotion recovery in injured cats.

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