scholarly journals Photobiomodulation inhibits the activation of neurotoxic microglia and astrocytes by inhibiting Lcn2/JAK2-STAT3 crosstalk after spinal cord injury in male rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xuankang Wang ◽  
Xin Li ◽  
Xiaoshuang Zuo ◽  
Zhuowen Liang ◽  
Tan Ding ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Male Rats ◽  
In Vitro Experiments ◽  
Post Injury ◽  
Stat3 Pathway ◽  
Cord Injury ◽  
Recovery Of Motor Function

Abstract Background Neurotoxic microglia and astrocytes begin to activate and participate in pathological processes after spinal cord injury (SCI), subsequently causing severe secondary damage and affecting tissue repair. We have previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM ameliorates neuroinflammation by modulating the activation of microglia and astrocytes after SCI. Methods Male Sprague–Dawley rats were randomly divided into three groups: a sham control group, an SCI + vehicle group and an SCI + PBM group. PBM was performed for two consecutive weeks after clip-compression SCI models were established. The activation of neurotoxic microglia and astrocytes, the level of tissue apoptosis, the number of motor neurons and the recovery of motor function were evaluated at different days post-injury (1, 3, 7, 14, and 28 days post-injury, dpi). Lipocalin 2 (Lcn2) and Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) signaling were regarded as potential targets by which PBM affected neurotoxic microglia and astrocytes. In in vitro experiments, primary microglia and astrocytes were irradiated with PBM and cotreated with cucurbitacin I (a JAK2-STAT3 pathway inhibitor), an adenovirus (shRNA-Lcn2) and recombinant Lcn2 protein. Results PBM promoted the recovery of motor function, inhibited the activation of neurotoxic microglia and astrocytes, alleviated neuroinflammation and tissue apoptosis, and increased the number of neurons retained after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also showed that Lcn2 and JAK2-STAT3 were mutually promoted and that PBM interfered with this interaction, inhibiting the activation of microglia and astrocytes. Conclusion Lcn2/JAK2-STAT3 crosstalk is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be suppressed by PBM.

Photobiomodulation Inhibits the Activation of Neurotoxic Microglia and Astrocytes Through Inhibiting the Crosstalk of Lcn2/JAK2-STAT3 after Spinal Cord Injury in Rats

2021 ◽  
Author(s):  
Xuankang Wang ◽  
Xin Li ◽  
Xiaoshuang Zuo ◽  
Zhuowen Liang ◽  
Zhe Wang ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Janus Kinase ◽  
Vehicle Group ◽  
Lipocalin 2 ◽  
Stat3 Pathway ◽  
Cord Injury ◽  
Recovery Of Motor Function

Abstract BackgroundIn situ microglia and astrocytes begin to activate and participate in neuroinflammation after spinal cord injury (SCI), and the high expression of lipocalin 2 (Lcn2) and the activation of the Janus kinase-2 (JAK2)-signal transducer and activator of transcription-3 (STAT3) pathway promote the polarization of activated microglia and astrocytes towards the neurotoxic phenotype (M1 microglia and A1 astrocytes). We previously reported that photobiomodulation (PBM) can promote functional recovery by reducing neuroinflammation after SCI, but the mechanism of PBM on the microglia and astrocytes involved is still unclear. Therefore, the purpose of this study was to explore the role of the Lcn2 and JAK2-STAT3 pathways in the activation of M1 and A1 and the mechanism by which PBM may play a therapeutic role.MethodsPBM intervention was performed every day after the SCI model was established, and the activation of microglia and astrocytes was observed at different time points post injury (1, 3, 7, 14, 28 dpi). The level of tissue apoptosis, the number of surviving neurons, the recovery of motor function, the level of Lcn2 and the activation of JAK2-STAT3 were evaluated in the PBM group and the vehicle group. M1 and A1 cells were irradiated with PBM in vitro, and the JAK2-STAT3 pathway inhibitor cucurbitacin I, adenovirus transfection and recombinant Lcn2 protein were cotreated with PBM to explore the mechanism of the activation of M1 and A1 and the underlying effect of PBM.ResultsPBM inhibited the activation of neurotoxic microglia and astrocytes, decreased secondary inflammation and tissue apoptosis, increased the number of neurons retained, and promoted the recovery of motor function after SCI. The upregulation of Lcn2 and the activation of the JAK2-STAT3 pathway after SCI were suppressed by PBM. In vitro experiments also proved that PBM can inhibit the activation of M1 microglia and A1 astrocytes, and the effect is related to the level of Lcn2 and the activation of the JAK2-STAT3 pathway.ConclusionThe crosstalk of Lcn2/JAK2-STAT3 is involved in the activation of neurotoxic microglia and astrocytes after SCI, and this process can be alleviated by PBM.

scholarly journals Photobiomodulation Promotes Repair Following Spinal Cord Injury by Regulating the Transformation of A1/A2 Reactive Astrocytes

2021 ◽  
Vol 15 ◽  
Author(s):  
Xuankang Wang ◽  
Zhihao Zhang ◽  
Zhijie Zhu ◽  
Zhuowen Liang ◽  
Xiaoshuang Zuo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Growth Factor ◽  
Motor Function ◽  
Function Analysis ◽  
Reactive Astrocytes ◽  
Male Rats ◽  
Dependent Manner ◽  
Astrocyte Activation ◽  
Cord Injury

After spinal cord injury (SCI), reactive astrocytes can be classified into two distinctive phenotypes according to their different functions: neurotoxic (A1) astrocytes and neuroprotective (A2) astrocytes. Our previous studies proved that photobiomodulation (PBM) can promote motor function recovery and improve tissue repair after SCI, but little is known about the underlying mechanism. Therefore, we aimed to investigate whether PBM contributes to repair after SCI by regulating the activation of astrocytes. Male rats subjected to clip-compression SCI were treated with PBM for two consecutive weeks, and the results showed that recovery of motor function was improved, the lesion cavity size was reduced, and the number of neurons retained was increased. We determined the time course of A1/A2 astrocyte activation after SCI by RNA sequencing (RNA-Seq) and verified that PBM inhibited A1 astrocyte activation and promoted A2 astrocyte activation at 7 days postinjury (dpi) and 14 dpi. Subsequently, potential signaling pathways related to A1/A2 astrocyte activation were identified by GO function analysis and KEGG pathway analysis and then studied in animal experiments and preliminarily analyzed in cultured astrocytes. Next, we observed that the expression of basic fibroblast growth factor (bFGF) and transforming growth factor-β (TGF-β) was upregulated by PBM and that both factors contributed to the transformation of A1/A2 astrocytes in a dose-dependent manner. Finally, we found that PBM reduced the neurotoxicity of A1 astrocytes to dorsal root ganglion (DRG) neurons. In conclusion, PBM can promote better recovery after SCI, which may be related to the transformation of A1/A2 reactive astrocytes.

4:40104. Experimental Distraction Spinal Cord Injury and Recovery of Motor Function

2006 ◽  
Vol 6 (5) ◽  
pp. 51S ◽  
Author(s):  
Mary K. Nagai ◽  
Kirk Dabney ◽  
Marina Ehrenshteyn ◽  
Dianna Willis ◽  
Jeffery Twiss
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Cord Injury ◽  
Recovery Of Motor Function

scholarly journals DEPENDENCE OF THE RESTORATIVE EFFECT OF MACROPOROUS POLY(N-[2-HYDROXYPROPYL]-METHACRYLAMIDE HYDROGEL ON THE SEVERITY OF EXPERIMENTAL LACERATIVE SPINAL CORD INJURY

2021 ◽  
Vol 127 (4) ◽  
pp. 8-21
Author(s):  
Ibrahim Abdallah ◽  
Volodymyr Мedvediev ◽  
Nataliya Draguntsova ◽  
Nana Voitenko ◽  
Vitaliy Tsymbaliuk
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Severe Trauma ◽  
Individual Characteristics ◽  
Male Rats ◽  
Study Results ◽  
Cord Injury ◽  
Hydroxypropyl Methacrylamide ◽  
Immediate Implantation

restoration of the spinal cord function presents a most severe biomedical issue nowadays. The aim of the study was to detect the macroporous poly(N-[2-hydroxypropyl]-methacrylamide hydrogel (PHPMA-hydrogel, HG) restorative effect dependence on the severity of the laceration spinal cord injury in young organisms. The male rats sample (~1-month-old, ~50 g, inbred Wistar line) was represented with 4 experimental groups: 1) spinal cord lateral hemisection at the level of ~Т12–Т13 segments (Sect; n=11); 2) spinal cord lateral hemiexcision ~1 mm long at the similar level (Exc; n=8); 3) spinal cord lateral hemisection at the similar level with immediate implantation of the hydrogel fragment into the trauma region (HGsect; n=11); 4) spinal cord lateral hemiexcision at the similar level with immediate implantation of the hydrogel fragment into the affected region (HGexс; n=6). The motor function and spasticity of the paretic hindlimb was estimated respectively by the technically modified Basso–Beattie–Bresnahan (ВВВ) and Ashworth, conditionally blinded to individual characteristics of all operated animals and previous study results. The observation lasted for ~5 months. The criteria of non-inclusion were as follows: the ipsilateral hindlimb function level in a week after the injury >9 points ВВВ, and the contralateral hindlimb function level during prolonged period ≤14 points ВВВ. The results were interpreted and presented according to the standardized time scale with interpolatory representation of the motor function and spasticity individual level in certain cases. Asymptotic stage differences between the studied groups and subgroups were stated during the first three weeks as well as in 8 weeks and 3 months after the injury. We found out that in a week after injury the motor function level in group Exc made up 0.9±0.5 points ВВВ, in group HGexc — 3.6±1.2 points, in group Sect — 5.9±1.1 points, in group HGsect — 6.0±1.0 points. In 5 months the motor function level in group Sect made up 9.5±1.0 points ВВВ, in group HGsect — 9.5±1.1 points, in group Exc — 0.8±0.3 points, in group HGexc — 4.5±1.8 points. At the same study stage the spasticity level in groups Sect and HGsect was, respectively, 0.8±0.2 and 0.8±0.3 points Ashworth, in group HGexc — 1.8±0.7 points, in group Exc — 3.6±0.3 points. Throughout the study no significant differences in groups Sect and HGsect have been detected, and in groups Exc і HGexc such differences were detected only in 5 weeks after the injury. The considerable difference of spasticity in groups Sect and HGsect was noted in 1 week after the injury, in groups HGexc and Exc — during first 2 months of the experiment. In groups Sect and Exc reliable difference of both motor function and spasticity level was found at all study stages. In groups HGsect and HGexc considerable difference of the motor function level was characteristic at all stages, except for the end of the 1st and 7th weeks, whereas spasticity level differences throughout the study remained insignificant. So, the tested hydrogel in young organisms shows positive effect only with severe trauma stages accompanied with extensive spinal cord defect.

scholarly journals Pathophysiological Changes and the Role of Notch-1 Activation After Decompression in a Compressive Spinal Cord Injury Rat Model

2021 ◽  
Vol 15 ◽  
Author(s):  
Xing Cheng ◽  
Zhengran Yu ◽  
Jinghui Xu ◽  
Daping Quan ◽  
Houqing Long
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Surgical Decompression ◽  
Cellular Damage ◽  
Notch 1 ◽  
Post Injury ◽  
Function Recovery ◽  
Cord Injury

Surgical decompression is the primary treatment for cervical spondylotic myelopathy (CSM) patients with compressive spinal cord injury (CSCI). However, the prognosis of patients with CSCI varies, and the pathophysiological changes following decompression remain poor. This study aimed to investigate the pathophysiological changes and the role of Notch-1 activation after decompression in a rat CSCI model. Surgical decompression was conducted at 1 week post-injury (wpi). DAPT was intraperitoneally injected to down-regulate Notch-1 expression. Basso, Beattie, and Bresnahan scores and an inclined plane test were used to evaluate the motor function recovery. Hematoxylin and eosin staining was performed to assess pathophysiological changes, while hypoxia-inducible factor 1 alpha, vascular endothelial growth factor (VEGF), von Willebrand factor (vWF), matrix metalloproteinase (MMP)-9, MMP-2, Notch-1, and Hes-1 expression in the spinal cord were examined by immunohistochemical analysis or quantitative PCR. The results show that early decompression can partially promote motor function recovery. Improvements in structural and cellular damage and hypoxic levels were also observed in the decompressed spinal cord. Moreover, decompression resulted in increased VEGF and vWF expression, but decreased MMP-9 and MMP-2 expression at 3 wpi. Expression levels of Notch-1 and its downstream gene Hes-1 were increased after decompression, and the inhibition of Notch-1 significantly reduced the decompression-induced motor function recovery. This exploratory study revealed preliminary pathophysiological changes in the compressed and decompressed rat spinal cord. Furthermore, we confirmed that early surgical decompression partially promotes motor function recovery may via activation of the Notch-1 signaling pathway after CSCI. These results could provide new insights for the development of drug therapy to enhance recovery following surgery.

scholarly journals TRIM32 affects the recovery of motor function following spinal cord injury through regulating proliferation of glia

Oncotarget ◽  
2017 ◽  
Vol 8 (28) ◽  
pp. 45380-45390 ◽  
Author(s):  
Qiang Fu ◽  
Ming-Ming Zou ◽  
Jian-Wei Zhu ◽  
Yan Zhang ◽  
Wen-Jin Chen ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Cord Injury ◽  
Recovery Of Motor Function

Mechanisms of Behavioral Changes After Spinal Cord Injury

2019 ◽  
Author(s):  
Karim Fouad ◽  
Abel Torres-Espín ◽  
Keith K. Fenrich
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Motor Function ◽  
Lesion Size ◽  
Behavioral Changes ◽  
Sensory Function ◽  
Wide Range ◽  
Cord Injury ◽  
New Treatment ◽  
Recovery Of Motor Function

Spinal cord injury results in a wide range of behavioral changes including impaired motor and sensory function, autonomic dysfunction, spasticity, and depression. Currently, restoring lost motor function is the most actively studied and sought-after goal of spinal cord injury research. This research is rooted in the fact that although self-repair following spinal cord injury in adult mammals is very limited, there can be some recovery of motor function. This recovery is strongly dependent on the lesion size and location as well as on neural activity of denervated networks activated mainly through physical activity (i.e., rehabilitative training). Recovery of motor function is largely due to neuroplasticity, which includes adaptive changes in spared and injured neural circuitry. Neuroplasticity after spinal cord injury is extensive and includes mechanisms such as moderate axonal sprouting, the formation of new synaptic connections, network remapping, and changes to neuron cell properties. Neuroplasticity after spinal cord injury has been described at various physiological and anatomical levels of the central nervous system including the brain, brainstem, and spinal cord, both above and below injury sites. The growing number of mechanisms underlying postinjury plasticity indicate the vast complexity of injury-induced plasticity. This poses important opportunities to further enhance and harness plasticity in order to promote recovery. However, the diversity of neuroplasticity also creates challenges for research, which is frequently based on mechanistically driven approaches. The appreciation of the complexity of neuronal plasticity and the findings that recovery is based on a multitude and interlinked adaptations will be essential in developing meaningful new treatment avenues.

Effect of vitamins C and E on recovery of motor function after spinal cord injury: systematic review and meta-analysis of animal studies

2019 ◽  
Vol 78 (6) ◽  
pp. 465-473 ◽  
Author(s):  
Mostafa Hosseini ◽  
Arash Sarveazad ◽  
Asrin Babahajian ◽  
Masoud Baikpour ◽  
Alexander R Vaccaro ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Vitamin E ◽  
Animal Models ◽  
Vitamin C ◽  
Motor Function ◽  
Animal Studies ◽  
Meta Analysis ◽  
Cord Injury ◽  
Recovery Of Motor Function

Abstract Context Many animal studies have evaluated the role of vitamins in the recovery of motor function after spinal cord injury, but their results have been contradictory and no consensus has been reached. Objective This meta-analysis aimed to investigate the effects of vitamin C and vitamin E on recovery of motor function after spinal cord injury in animal models. Data Sources Two authors independently collected the records of relevant articles published in MEDLINE, Embase, Scopus, and Web of Science through November 2018. Study Selection All studies conducted in animal models to evaluate the therapeutic effects of vitamin C or vitamin E or both on recovery of motor function after spinal cord injury were included. Studies that lacked a control group or a standard treatment, lacked an assessment of motor function, included genetically modified/engineered animals, included animals pretreated with vitamin C or vitamin E, or combined vitamin treatment with other methods, such as cell therapies, were excluded. Data Extraction Data from 10 articles met the inclusion criteria for meta-analysis, conducted in accordance with PRISMA guidelines. Results Daily supplementation with vitamin C (P < 0.0001) and vitamin E (P < 0.0001) significantly improved the recovery of motor function in animals affected by spinal cord injury. Vitamin C supplementation is effective only when administered intraperitoneally (P < 0.0001). Concurrent supplementation with both vitamins does not show better efficacy than treatment with either one alone. Conclusion Administration of vitamin C and vitamin E in animal models of spinal cord injury significantly improves the recovery of motor function.

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