scholarly journals Leucine rich repeats and calponin homology domain containing 1 inhibits microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model

2019 ◽  
Author(s):  
Wen-Kai Chen ◽  
Lin-Juan Feng ◽  
Qiao-Dan Liu ◽  
Qing-Feng Ke ◽  
Pei-Ya Cai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Cytokines ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Neuron Death ◽  
Microglial Polarization ◽  
Cord Injury ◽  
Pro Inflammatory Cytokines

Abstract Background Spinal cord injury (SCI) triggers the primary mechanical injury and secondary inflammation-mediated injury. Neuroinflammation-mediated insult causes secondary and extensive neurological damage after SCI. Microglia play a pivotal role in the initiation and progression of post-SCI neuroinflammation.Methods To elucidate the significance of LRCH1 to microglial functions, we applied lentivirus-induced LRCH1 knockdown in primary microglia culture, and tested the role of LRCH1 in microglia-mediated inflammatory reaction both in vitro and in a rat SCI model.ResultsWe found that LRCH1 was down-regulated in microglia after traumatic SCI. LRCH1 knockdown increased the production of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 after in vitro priming with lipopolysaccharide and adenosine triphosphate. Furthermore, LRCH1 knockdown promoted the priming-induced microglial polarization towards the pro-inflammatory M1 type, as demonstrated by increased differentiation into inducible nitric oxide synthase (iNOS)+ microglia. LRCH1 knockdown also enhanced microglia-mediated N27 neuron death after priming. Further analysis revealed that LRCH1 knockdown increased priming-induced activation of p38 mitogen-activated protein kinase (MAPK) and Erk1/2 signaling, which are crucial for M1 polarization of microglia. When LRCH1-knockdown microglia were adoptively injected into rat spinal cords, they enhanced post-SCI production of pro-inflammatory cytokines, increased SCI-induced recruitment of leukocytes, aggravated SCI-induced tissue damage and neuronal death, and worsened the locomotor function.Conclusion Our study reveals for the first time that LRCH1 serves as a negative regulator of microglia-mediated neuroinflammation after SCI, and provides clues for developing novel therapeutic approaches against SCI.

scholarly journals Leucine rich repeats and calponin homology domain containing 1 inhibits microglia-mediated neuroinflammation in a rat traumatic spinal cord injury model

2020 ◽  
Author(s):  
Wen-Kai Chen ◽  
Lin-Juan Feng ◽  
Qiao-Dan Liu ◽  
Qing-Feng Ke ◽  
Pei-Ya Cai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Cytokines ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Neuron Death ◽  
Microglial Polarization ◽  
Cord Injury ◽  
Pro Inflammatory Cytokines

Abstract Background Spinal cord injury (SCI) triggers the primary mechanical injury and secondary inflammation-mediated injury. Neuroinflammation-mediated insult causes secondary and extensive neurological damage after SCI. Microglia play a pivotal role in the initiation and progression of post-SCI neuroinflammation. Methods To elucidate the significance of LRCH1 to microglial functions, we applied lentivirus-induced LRCH1 knockdown in primary microglia culture, and tested the role of LRCH1 in microglia-mediated inflammatory reaction both in vitro and in a rat SCI model. Results We found that LRCH1 was down-regulated in microglia after traumatic SCI. LRCH1 knockdown increased the production of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6 after in vitro priming with lipopolysaccharide and adenosine triphosphate. Furthermore, LRCH1 knockdown promoted the priming-induced microglial polarization towards the pro-inflammatory inducible nitric oxide synthase (iNOS)-expressing microglia. LRCH1 knockdown also enhanced microglia-mediated N27 neuron death after priming. Further analysis revealed that LRCH1 knockdown increased priming-induced activation of p38 mitogen-activated protein kinase (MAPK) and Erk1/2 signaling, which are crucial to the inflammatory response of microglia. When LRCH1-knockdown microglia were adoptively injected into rat spinal cords, they enhanced post-SCI production of pro-inflammatory cytokines, increased SCI-induced recruitment of leukocytes, aggravated SCI-induced tissue damage and neuronal death, and worsened the locomotor function. Conclusion Our study reveals for the first time that LRCH1 serves as a negative regulator of microglia-mediated neuroinflammation after SCI, and provides clues for developing novel therapeutic approaches against SCI.

scholarly journals Chirality-Dependent Anti-Inflammatory Effect of Glutathione after Spinal Cord Injury in an Animal Model

2021 ◽  
Vol 14 (8) ◽  
pp. 792
Author(s):  
Seong-Jun Kim ◽  
Wan-Kyu Ko ◽  
Gong-Ho Han ◽  
Daye Lee ◽  
Yuhan Lee ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Specific Interaction ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Secondary Damage ◽  
Cord Injury ◽  
Mitogen Activated Protein ◽  
Pro Inflammatory Cytokines

Neuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. Molecular chirality can show an entirely different bio-function by means of chiral-specific interaction. In this study, we report that d-chiral glutathione (D-GSH) suppresses the inflammatory response after SCI and leads to axon regeneration of the injured spinal cord to a greater extent than l-chiral glutathione (L-GSH). After SCI, axon regrowth in D-GSH-treated rats was significantly increased compared with that in L-GSH-treated rats (*** p < 0.001). Secondary damage and motor function were significantly improved in D-GSH-treated rats compared with those outcomes in L-GSH-treated rats (** p < 0.01). Moreover, D-GSH significantly decreased pro-inflammatory cytokines and glial fibrillary acidic protein (GFAP) via inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway compared with L-GSH (*** p < 0.001). In primary cultured macrophages, we found that D-GSH undergoes more intracellular interaction with activated macrophages than L-GSH (*** p < 0.001). These findings reveal a potential new regenerative function of chiral GSH in SCI and suggest that chiral GSH has therapeutic potential as a treatment of other diseases.

scholarly journals Chirality-dependent anti-inflammatory effect of glutathione after spinal cord injury

2020 ◽  
Author(s):  
Seong Jun Kim ◽  
Wan-Kyu Ko ◽  
Gong Ho Han ◽  
Daye Lee ◽  
Yuhan Lee ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Therapeutic Potential ◽  
Mapk Signaling ◽  
Glial Scar ◽  
Mitogen Activated Protein Kinase ◽  
Secondary Damage ◽  
Cord Injury ◽  
Mitogen Activated Protein ◽  
Pro Inflammatory Cytokines

AbstractNeuroinflammation forms a glial scar following a spinal cord injury (SCI). The injured axon cannot regenerate across the scar, suggesting permanent paraplegia. In this study, we report that d-chiral glutathione (D-GSH) suppresses the inflammatory response after SCI and leads to axon regeneration of the injured spinal cord to a greater extent than l-chiral glutathione (L-GSH). After SCI, axon regrowth in D-GSH-treated rats was significantly increased compared to that in L-GSH-treated rats (***p < 0.001). Secondary damage and motor function were significantly improved in D-GSH-treated rats compared to those outcomes in L-GSH-treated rats (**p < 0.01). Moreover, D-GSH significantly decreased pro-inflammatory cytokines and glial scar via inhibition of the mitogen-activated protein kinase (MAPK) signaling pathway compared to L-GSH (***p < 0.001). In primary cultured macrophages, we found that D-GSH undergoes more intracellular interaction with activated macrophages than L-GSH (***p < 0.001). These findings reveal a potential new regenerative function of chiral GSH in SCI and suggest that chiral GSH has therapeutic potential as a treatment of other diseases.

Effects of Tetramethylpyrazine on Microglia Activation in Spinal Cord Compression Injury of Mice

2013 ◽  
Vol 41 (06) ◽  
pp. 1361-1376 ◽  
Author(s):  
Jung-Won Shin ◽  
Ja-Young Moon ◽  
Ju-Won Seong ◽  
Sang-Hoon Song ◽  
Young-Jin Cheong ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Cytokines ◽  
Spinal Cord Compression ◽  
Cord Compression ◽  
Microglia Activation ◽  
Compression Injury ◽  
Neuroprotective Effects ◽  
Cord Injury ◽  
Pro Inflammatory Cytokines

Secondary mechanisms, including inflammation and microglia activation, serve as targets for the development and application of pharmacological strategies in the management of spinal cord injury (SCI). Tetramethylpyrazine (TMP), an active ingredient of Ligusticum wallichii (chuanxiong), has shown anti-inflammatory and neuroprotective effects against SCI. However, it remains uncertain whether the inflammation-suppressive effects of TMP play a modulatory role over microglia activation in SCI. The present study investigated the effects of TMP on microglia activation and pro-inflammatory cytokines in spinal cord compression injury in mice. For a real-time PCR measurement of pro-inflammatory cytokines, SCI was induced in mice by the clip compression method (30 g force, 1 min) and TMP (15 or 30 mg/kg, i.p.) was administered once, 30 minutes before the SCI induction. For immunohistochemistry, TMP (30 mg/kg, i.p.) treatment was given three times during the first 48 hours after the SCI. 30 mg/kg of TMP treatment reduced the up-regulation of TNF-α, IL-1β and COX-2 mRNA in the spinal tissue at four hours after the SCI induction. TMP also significantly attenuated microglia activation and neutrophil infiltration at 48 hours after the SCI induction. In addition, iNOS expression in the spinal tissue was attenuated with TMP treatment. These results suggest that TMP plays a modulatory role in microglia activation and may protect the spinal cord from or potentially delay secondary spinal cord injury.

scholarly journals Lysine-specific demethylase 1 inhibition enhances autophagy and attenuates early-stage post-spinal cord injury apoptosis

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yang Gu ◽  
Dehui Chen ◽  
Linquan Zhou ◽  
Xin Zhao ◽  
Jiemin Lin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Cellular Response ◽  
Early Stage ◽  
Potential Candidate ◽  
Neuron Death ◽  
Damage Models ◽  
Lysine Specific Demethylase ◽  
Cord Injury

AbstractNeuron death in spinal cords is caused primarily by apoptosis after spinal cord injury (SCI). Autophagy can act as a cellular response to maintain neuron homeostasis that can reduce apoptosis. Although more studies have shown that an epigenetic enzyme called Lysine-specific demethylase 1 (LSD1) can negatively regulate autophagy during cancer research, existing research does not focus on impacts related to LSD1 in nerve injury diseases. This study was designed to determine whether inhibiting LSD1 could enhance autophagy against apoptosis and provide effective neuroprotection in vitro and vivo after SCI. The results showed that LSD1 inhibition treatment significantly reduced spinal cord damage in SCI rat models and was characterized by upregulated autophagy and downregulated apoptosis. Further research demonstrated that using both pharmacological inhibition and gene knockdown could enhance autophagy and reduce apoptosis for in vitro simulation of SCI-caused damage models. Additionally, 3-methyladenine (3-MA) could partially eliminate the effect of autophagy enhancement and apoptosis suppression. These findings demonstrated that LSD1 inhibition could protect against SCI by activating autophagy and hindering apoptosis, suggesting a potential candidate for SCI therapy.

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