Modulation of the secondary injury process after spinal cord injury in Bach1-deficient mice by heme oxygenase–1

2008 ◽  
Vol 9 (6) ◽  
pp. 611-620 ◽  
Author(s):  
Kiyotaka Yamada ◽  
Nobuhiro Tanaka ◽  
Kazuyoshi Nakanishi ◽  
Naosuke Kamei ◽  
Masakazu Ishikawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Heme Oxygenase ◽  
Blue Staining ◽  
Heme Oxygenase 1 ◽  
Secondary Injury ◽  
Wild Type ◽  
Early Stages ◽  
Cord Injury

Object Oxidative stress contributes to secondary injury after spinal cord injury (SCI). The expression of heme oxygenase-1 (HO-1), which protects cells from various insults including oxidative stress, is upregulated in injured spinal cords. Mice deficient in Bach1 (Bach1−/−), a transcriptional repressor of the HO-1 and beta-globin genes, express high levels of HO-1 mRNA and protein in various organs. The authors hypothesized that HO-1 modulates the secondary injury process after SCI in Bach1−/− mice. Methods Male C57BL/6 (wild-type) and homozygous Bach1−/− C57BL/6 mice were subjected to moderate SCI, and differences in hindlimb motor function, and electrophysiological, molecular biological, and histopathological changes were assessed for 2 weeks. Results Functional recovery was greater, and motor evoked potentials were significantly larger in Bach1−/− mice than in wild-type mice throughout the observation period. The expression of HO-1 mRNA in the spinal cord was significantly increased in both mice until 3 days after injury, and it was significantly higher in Bach1−/− mice than in wild-type mice at every assessment point. Histological examination using Luxol fast blue staining at 1 day after injury showed that the injured areas were smaller in Bach1−/− mice than in wild-type mice. The HO-1 immunoreactivity was not detected in uninjured spinal cord, but 3 days postinjury the number of HO-1–immunoreactive cells was obviously higher in the injured area in both mice, particularly in Bach1−/− mice. The HO-1 was primarily induced in microglia/macrophage in both mice. Conclusions These results suggest that HO-1 modulates the secondary injury process, and high HO-1 expression may preserve spinal cord function in the early stages after SCI in Bach1−/− mice. Treatment that induces HO-1 expression at these early stages may preserve the functional outcome after SCI.

scholarly journals CCL3 contributes to secondary damage after spinal cord injury

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Nicolas Pelisch ◽  
Jose Rosas Almanza ◽  
Kyle E. Stehlik ◽  
Brandy V. Aperi ◽  
Antje Kroner
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Lesion Size ◽  
Secondary Injury ◽  
Wild Type ◽  
Locomotor Recovery ◽  
Secondary Damage ◽  
Cord Injury

Abstract Background Secondary damage after spinal cord injury (SCI) is characterized by a cascade of events including hemorrhage, apoptosis, oxidative stress, and inflammation which increase the lesion size which can influence the functional impairment. Thus, identifying specific mechanisms attributed to secondary injury is critical in minimizing tissue damage and improving neurological outcome. In this work, we are investigating the role of CCL3 (macrophage inflammatory protein 1-α, MIP-1α), a chemokine involved in the recruitment of inflammatory cells, which plays an important role in inflammatory conditions of the central and peripheral nervous system. Methods A mouse model of lower thoracic (T11) spinal cord contusion injury was used. We assessed expression levels of CCL3 and its receptors on the mRNA and protein level and analyzed changes in locomotor recovery and the inflammatory response in the injured spinal cord of wild-type and CCL3−/− mice. Results The expression of CCL3 and its receptors was increased after thoracic contusion SCI in mice. We then examined the role of CCL3 after SCI and its direct influence on the inflammatory response, locomotor recovery and lesion size using CCL3−/− mice. CCL3−/− mice showed mild but significant improvement of locomotor recovery, a smaller lesion size and reduced neuronal damage compared to wild-type controls. In addition, neutrophil numbers as well as the pro-inflammatory cytokines and chemokines, known to play a deleterious role after SCI, were markedly reduced in the absence of CCL3. Conclusion We have identified CCL3 as a potential target to modulate the inflammatory response and secondary damage after SCI. Collectively, this study shows that CCL3 contributes to progressive tissue damage and functional impairment during secondary injury after SCI.

scholarly journals Effect of canine mesenchymal stromal cells overexpressing heme oxygenase-1 in spinal cord injury

2017 ◽  
Vol 18 (3) ◽  
pp. 377 ◽  
Author(s):  
Seung Hoon Lee ◽  
Yongsun Kim ◽  
Daeun Rhew ◽  
Ahyoung Kim ◽  
Kwang Rae Jo ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Heme Oxygenase ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Heme Oxygenase 1 ◽  
Cord Injury

Heme Oxygenase–1 Expression after Spinal Cord Injury: The Induction in Activated Neutrophils

2002 ◽  
Vol 19 (4) ◽  
pp. 479-490 ◽  
Author(s):  
Yi Liu ◽  
Toshiya Tachibana ◽  
Yi Dai ◽  
Eiji Kondo ◽  
Tetsuo Fukuoka ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Heme Oxygenase ◽  
Heme Oxygenase 1 ◽  
Cord Injury ◽  
Activated Neutrophils

scholarly journals Astrocytic Nrf2 Expression Protects Spinal Cord From Oxidative Stress in a Spinal Cord Injury Animal Model

2021 ◽  
Author(s):  
Weiyi Zhao ◽  
Natalie Gasterich ◽  
Tim Clarner ◽  
Clara Voelz ◽  
Victoria Behrens ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Stress Responses ◽  
Neuronal Damage ◽  
Related Factor ◽  
Wild Type ◽  
Promising Therapeutic Approach ◽  
Cord Injury ◽  
The Impact

Abstract BackgroundSpinal cord injury (SCI) induces a multitude of deleterious processes, including neuroinflammation and oxidative stress (OS) which contributed to neuronal damage and demyelination. Recent studies have suggested that increased formation of reactive oxygen species (ROS) and the consequent OS are critical events associated with SCI. However, there is still little information regarding the impact of these events on SCI. Astrocytes are key regulators of oxidative homeostasis in the CNS and astrocytic antioxidant responses promote the clearance of oxidants produced by neurons. Therefore, dysregulation of astrocyte physiology might largely contribute to oxidative damage. Nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of cellular anti-oxidative stress responses. MethodsIn the current study, using mice with a GFAP-specific kelch-like ECH-associated protein 1 (Keap1)-deletion, we induced a hyperactivation of Nrf2 in astrocytes and further its effects on SCI outcomes. SCI-induction was performed in mice using the Infinite Horizon Spinal Cord Impactor with a force of 60 kdyn. To assess the quantitative pattern of Nrf2/ARE-activation, we included transgenic ARE-Luc mice. Data were analyzed with GraphPad Prism 8 (GraphPad Software Inc., San Diego, CA, USA). Brown-Forsythe test was performed to test for equal variances and normal distribution was tested with Shapiro-Wilk.ResultsIn ARE-Luc mice, a significant induction of luciferase-activity was observed as early as 1 day post injury, indicating a functional role of Nrf2-activity at the epicenter of SCI. Further, SCI induced loss of neurons and oligodendrocytes, demyelination and inflammation in wild type mice. The loss of myelin and oligodendrocytes was clearly reduced in Keap1 KO mice. In addition, Keap-1 KO mice showed a significantly better locomotor function and lower neuroinflammation responses compared to wild type mice. ConclusionsIn summary, our in vivo bioluminescence data showed Nrf2-ARE activation during primary phase of SCI. Further, we found that cell specific hyperactivation of Nrf2 was sufficient to protect the spinal cord against injury which indicate a promising therapeutic approach for SCI-treatment.

scholarly journals Sirtuins: Potential Therapeutic Targets for Defense against Oxidative Stress in Spinal Cord Injury

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Jialiang Lin ◽  
Zhencheng Xiong ◽  
Jionghui Gu ◽  
Zhuoran Sun ◽  
Jiang Shuai ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Pathological Process ◽  
Secondary Injury ◽  
Beneficial Effects ◽  
Cord Injury ◽  
Primary Injury ◽  
Antioxidant Mechanisms ◽  
Antioxidant Effects

Spinal cord injury (SCI) is one of the most incapacitating neurological disorders. It involves complex pathological processes that include a primary injury and a secondary injury phase, or a delayed stage, which follows the primary injury and contributes to the aggravation of the SCI pathology. Oxidative stress, a key pathophysiological event after SCI, contributes to a cascade of inflammation, excitotoxicity, neuronal and glial apoptosis, and other processes during the secondary injury phase. In recent years, increasing evidence has demonstrated that sirtuins are protective toward the pathological process of SCI through a variety of antioxidant mechanisms. Notably, strategies that modulate the expression of sirtuins exert beneficial effects in cellular and animal models of SCI. Given the significance and novelty of sirtuins, we summarize the oxidative stress processes that occur in SCI and discuss the antioxidant effects of sirtuins in SCI. We also highlight the potential of targeting sirtuins for the treatment of SCI.

Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis

2017 ◽  
Vol 34 (3) ◽  
pp. 695-706 ◽  
Author(s):  
Wenping Lin ◽  
Siyuan Wang ◽  
Zhen Yang ◽  
Jianhua Lin ◽  
Qingfeng Ke ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Heme Oxygenase ◽  
Neuronal Apoptosis ◽  
Heme Oxygenase 1 ◽  
Down Regulation ◽  
Cord Injury

Therapeutic targets and nanomaterial-based therapies for mitigation of secondary injury after spinal cord injury

Nanomedicine ◽  
2021 ◽  
Vol 16 (22) ◽  
pp. 2013-2028
Author(s):  
Jun Gao ◽  
Minkyung Khang ◽  
Zhen Liao ◽  
Megan Detloff ◽  
Jeoung Soo Lee
Keyword(s):  
Oxidative Stress ◽  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Inflammatory Response ◽  
Therapeutic Targets ◽  
Neurological Dysfunction ◽  
Secondary Injury ◽  
Cord Injury ◽  
Blood Spinal Cord Barrier ◽  
And Oxidative Stress

Spinal cord injury (SCI) and the resulting neurological trauma commonly result in complete or incomplete neurological dysfunction and there are few effective treatments for primary SCI. However, the following secondary SCI, including the changes of microvasculature, inflammatory response and oxidative stress around the injury site, may provide promising therapeutic targets. The advances of nanomaterials hold promise for delivering therapeutics to alleviate secondary SCI and promote functional recovery. In this review, we highlight recent achievements of nanomaterial-based therapy, specifically targeting blood–spinal cord barrier disruption, mitigation of the inflammatory response and lightening of oxidative stress after spinal cord injury.

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