Plumbagin Protects Against Spinal Cord Injury-induced Oxidative Stress and Inflammation in Wistar Rats through Nrf-2 Upregulation

Zhang, W.; Cheng, Lin; Hou, Yong; Si, Meng; Zhao, Yu; Lin, Na

doi:10.1055/s-0034-1389950

Cited by 21 publications

(29 citation statements)

References 18 publications

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“…Oxidative stress‐induced inflammatory response is one of the major events in secondary injury; which ultimately leads to apoptosis with eventual loss of neurological function . Emerging evidence indicates that oxidative stress and inflammatory responses play critical role in SCI . Following SCI, the normally quiescent microglia are inevitably activated, with changes in morphology, proliferation, and release of cytokines and chemokines, finally becoming so‐called ‘reactive microglia’ .…”

Section: Discussionmentioning

confidence: 99%

“…22 Emerging evidence indicates that oxidative stress and inflammatory responses play critical role in SCI. 23,24 Following SCI, the normally quiescent microglia are inevitably activated, with changes in morphology, proliferation, and release of cytokines and chemokines, finally becoming so-called 'reactive microglia'. 25,26 As shown in this study, we found that proinflammatory MiRNAs are tiny endogenous RNAs that regulate gene expression at the post-transcriptional level and are capable of controlling specific cellular and physiological processes.…”

Section: Discussionmentioning

confidence: 99%

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MiR‐30a‐5p ameliorates spinal cord injury‐induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling

Shen

Wang

et al. 2017

Clin Exp Pharma Physio

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SummarySpinal cord injury (SCI) is a major disability requiring more effective treatment than is currently available. MicroRNAs have been shown to effectively regulate gene expression at the translational level. The aim of the present study was to explore the potential role of miR-30-5p and possible mechanism in SCI. We found that miR-30-5p was notably down-regulated, while Neurod 1 expression was highly elevated in microglia from the mouse model of SCI. Additionally, overexpression of miR-30a-5p significantly suppressed inflammatory responses as reflected by a decrease in the secretion of the cytokines TNF-α, IL-1β and IL-10 triggered by SCI. Furthermore, introduction of miR30a-5p strengthened the scavenging of oxygen free radicals accompanied by an increase in the expression of SEPN1, TXNL1 and GPX1. More importantly, our study explored that Neurod 1 was a direct and functional target of miR-30a-5p, which was validated by the dual luciferase reporter assay. qRT-PCR and western blot analysis further validated that miR-30a-5p negatively regulated the expression of Neurod 1.Mechanistically, overexpression of miR-30a-5p or silencing of the Neurod 1 gene prevented the MAPK/ERK signalling and inhibited inflammatory responses, meanwhile activated SEPN1, TXNL1 and GPX1. These findings indicate that miR-30a-5p ameliorates inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling. K E Y W O R D Sinflammatory, MAPK/ERK signalling, miR-30a-5p, Neurod 1, oxidative stress, spinal cord injury miR-30a regulates ischemia-induced neuronal cell death by targeting heat shock protein HSPA5 in primary cultured cortical neurons and mouse brain after stroke. 9 There is also increasing evidence that miRNAs are involved in the pathogenesis of SCI in a rat contusion SCI model, with miR-30a-5p emerging as one of the deregulated miR- | INTRODUCTION NAs.10 However, the role of miR-30a-5p in SCI is not well understood.Neurod 1 is predominantly expressed in the nervous system late in development and is therefore likely to be involved in terminal differentiation, neuronal maturation and survival. It has been reported that Neurod 1 is essential for the survival and maturation of adultborn neurons. 11 MAPK/ERK signalling is a well-defined pathway that is directly associated with cell growth, proliferation, and survival. 12,13Inhibition of MAPK suppresses microglia activation and associated cytokine production, and reduces neuro-inflammation-associated secondary damage. 12 For example, the activation of MAPK has been reported to be essential for the production of several inflammatory cytokines, such as IL-1β and IL-6. 12Based on this research background, we analyzed possible immunoregulatory mechanisms of miR-30a-5p and the Neurod 1/MAPK/ ERK signalling pathway in mice microglia induced by spinal cord injury.We found that miR-30a-5p was down-regulated and directly bound to the 3′-UTR of Neurod 1. MiR-30a-5p regulated inflammatory responses and oxidative stress by regulating Neurod 1 through MAPK/ ERK signallin...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

MiR‐30a‐5p ameliorates spinal cord injury‐induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling

Shen

Wang

et al. 2017

Clin Exp Pharma Physio

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“…The neuroprotective effect of PL has been explained by its potential to activate Nrf2 (Chu et al, 2016; Son et al, 2010). Up-regulated Nrf2 protects the brain against blood-brain barrier breakdown (Alfieri et al, 2011), spinal cord injury (Zhang et al, 2015) and cerebral ischemia (Son et al, 2010). Therefore, Nrf2 may have a protective role in neurodegenerative diseases, including PD (Choi et al, 2012; Cuadrado et al, 2009), AD (Kanninen et al, 2008), and HD (Stack et al, 2010) as well as traumatic brain injury (Yan et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Several investigations showed that PL inhibits NF-κB (Checker et al, 2009; Luo et al, 2010; T. Wang et al, 2014; Zhang et al, 2015) and the pro-inflammatory cytokines stimulated by NF-κB activation in the in vivo models of osteoporosis (Zheng et al, 2017). Furthermore, the protective effects of PL through inhibition of LPS-induced NO, cytokines and NF-κB release in mice and RAW 264.7 macrophage cells were reported (Checker et al, 2014; T.…”

Section: Introductionmentioning

confidence: 99%

The attenuating effects of plumbagin on pro-inflammatory cytokine expression in LPS-activated BV-2 microglial cells

Messeha

Zarmouh

Mendonca

et al. 2017

Journal of Neuroimmunology

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Activated microglial cells produce the pro-inflammatory mediators such as nitric oxide (NO) and cytokines. The excessive release of these mediators can lead to neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Inhibition of the release of these pro-inflammatory molecules may prevent or halt the progression of these diseases. Plumbagin (PL), a naphthoquinone compound in the roots of the traditional medicinal plant Plumbago zeylanica L., showed anti-inflammatory effects on macrophages. However, PL effects on activated microglia remain unknown. In the present study, PL has been examined for its anti-inflammatory effect on LPS – activated microglial BV-2 cells. In this study, NO and iNOS expression were investigated in BV-2 microglial cells in the presence of PL or the selective iNOS inhibitor L-N6-(1-iminoethyl) lysine (L-NIL). The results obtained indicate that PL was > 30-fold potent than L-NIL in inhibiting NO production with an IC50 of 0.39 μM. Our immunofluorescence study confirmed the ability of PL to significantly inhibit iNOS expression in the activated microglia. Furthermore, the extracellular microglial pro-inflammatory cytokine expression in the presence of 2 μM of PL was detected, quantified, and validated using cytokine antibody protein arrays and quantitative ELISA. The results obtained showed that PL significantly downregulated the expression of many cytokines including IL-1α, G-CSF, IL-12 p40/p70, MCP-5, MCP-1, and IL-6. In conclusion, PL potency in attenuating multiple pro-inflammatory agents indicates its potential to be used for neurodegenerative diseases.

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“…Early relief of inflammation following SCI is involved in neural protection and the promotion of functional recovery. Nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α and interleukin (IL)-1β have been reported to be significantly downregulated following plumbagin treatment in SCI rats (9). Nacar et al (10) revealed the beneficial effect of atorvastatin in rat SCI through anti-inflammatory effects.…”

Section: Introductionmentioning

confidence: 99%

Asiaticoside attenuates the effects of spinal cord injury through antioxidant and anti-inflammatory effects, and inhibition of the p38-MAPK mechanism

Luo

Wang

et al. 2012

Molecular Medicine Reports

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Asiaticoside has potent pharmacological activity and broader pharmacological effects, including anti‑oxidant, antidepressant and hepatic protection effects, and the inhibition of tumor cell proliferation. However, the mechanism underlying the effects of asiaticoside on neurological pain in spinal cord injury (SCI) remain to be fully elucidated. Therefore, the present study investigated the specific mechanism underlying the beneficial action of asiaticoside in a SCI rat model. In the present study, Basso, Beattie and Bresnahan scores was determined to analyze the therapeutic effects of asiaticoside on the neurological function of the SCI rat model. The water content of the spinal cord was also determined to measure its effects on the SCI rats. Oxidative stress, levels of nitric oxide and inflammation were detected using commercial kits. Western blot analysis was used to measure the protein expression levels of p38‑mitogen‑activated protein kinase (MAPK) in the SCI rat. Asiaticoside effectively augmented the Basso, Beattie and Bresnahan scores of the SCI rats. Significant reductions in the water content of the spinal cord, the levels of inducible nitric oxide synthase (iNOS), and the activities of the nuclear factor‑κB p65 unit, tumor necrosis factor‑α, interleukin(IL)‑1β and IL‑6 were observed in the experimental animals. Furthermore, on examination of the oxidative stress‑associated parameters, increased production of malondialdehyde and decreased levels of superoxide dismutase, glutathione and glutathione peroxidase were detected in the SCI rat model. Asiaticoside also significantly suppressed the expression of p38‑MAPK, which indicated that the therapeutic effects of asiaticoside may be associated with the p38‑MAPK pathway. These data confirmed that asiaticoside attenuates SCI through antioxidant and anti‑inflammatory effects, and through inhibition of the p38‑MAPK mechanism.

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Plumbagin Protects Against Spinal Cord Injury-induced Oxidative Stress and Inflammation in Wistar Rats through Nrf-2 Upregulation

Abstract: Taken together, the data suggests potential and novel role of Plumbagin in cytoprotection by modulating NF-κB and Nrf-2 levels against spinal cord injury.

Cited by 21 publications

References 18 publications

MiR‐30a‐5p ameliorates spinal cord injury‐induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling

MiR‐30a‐5p ameliorates spinal cord injury‐induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling

The attenuating effects of plumbagin on pro-inflammatory cytokine expression in LPS-activated BV-2 microglial cells

Asiaticoside attenuates the effects of spinal cord injury through antioxidant and anti-inflammatory effects, and inhibition of the p38-MAPK mechanism

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