Disruption of Nrf2 exacerbated the damage after spinal cord injury in mice

Mao, Lei; Wang, Handong; Wang, Xiaoliang; Tian, Lei; Xu, Jian-Ya

doi:10.1097/ta.0b013e31821bf541

Cited by 39 publications

(27 citation statements)

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“…While our work was in progress, two sets of researchers reported that SF treatment of rodents subjected to SCI leads to improvements in functional and anatomical recovery. 24,25 These studies are in full agreement with our findings that SF treatment after SCI improves hindlimb behavioral outcomes. Furthermore, increases in serotonergic axons caudal to the lesion site in injured SF-treated rats suggest a further protective role for SF administration after SCI.…”

supporting

confidence: 90%

“…25 In our study SF treatment significantly increased expression of the quintessential Nrf2 markers NQO1 and HO-1 at 4 h after contusive SCI. The importance of the Nrf2 pathway in SFmediated protection against SCI has been established in Nrf2 knockout mice, 24,38 which showed increased edema and inflammation (IL-6 and IL-1b protein), and increased neuronal death in the injured spinal cord, and more severe hindlimb motor dysfunction with no improvements upon SF treatment. 24,38 In wildtype mice, acute treatment with SF leads to protective effects, including decreased edema and fewer dying neurons in the spinal cord 48 h after injury, and improved hindlimb motor function during the first week after injury.…”

Section: Discussionmentioning

confidence: 99%

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Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Benedict

Mountney

Hurtado

et al. 2012

Journal of Neurotrauma

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Traumatic spinal cord injury (SCI) leads to oxidative stress, calcium mobilization, glutamate toxicity, the release of proinflammatory factors, and depletion of reduced glutathione (GSH) at the site of injury. Induction of the Keap1/Nrf2/ ARE pathway can alleviate neurotoxicity by protecting against GSH depletion, oxidation, intracellular calcium overload, mitochondrial dysfunction, and excitotoxicity. Sulforaphane (SF), an isothiocyanate derived from broccoli, is a potent naturally-occurring inducer of the Keap1/Nrf2/ARE pathway, leading to upregulation of genes encoding cytoprotective proteins such as NAD(P)H: quinone oxidoreductase 1, and GSH-regulatory enzymes. Additionally, SF can attenuate inflammation by inhibiting the nuclear factor-jB (NF-jB) pathway, and the enzymatic activity of the proinflammatory cytokine macrophage inhibitory factor (MIF). Our study examined systemic administration of SF in a rat model of contusion SCI, in an effort to utilize its indirect antioxidant and anti-inflammatory properties to decrease secondary injury. Two doses of SF (10 or 50 mg/kg) were administered at 10 min and 72 h after contusion SCI. SF (50 mg/kg) treatment resulted in both acute and long-term beneficial effects, including upregulation of the phase 2 antioxidant response at the injury site, decreased mRNA levels of inflammatory cytokines (i.e., MMP-9) in the injured spinal cord, inactivation of urinary MIF tautomerase activity, enhanced hindlimb locomotor function, and an increased number of serotonergic axons caudal to the lesion site. These findings demonstrate that SF provides neuroprotective effects in the spinal cord after injury, and could be a candidate for therapy of SCI.

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supporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Benedict

Mountney

Hurtado

et al. 2012

Journal of Neurotrauma

View full text Add to dashboard Cite

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“…Mice having Nrf2 deficiency exhibit consistent impairment in locomotor functions after compression [95,98] and contusion SCI [97] . One of the main factors responsible for the diminished recovery of motor functions after SCI is demyelination, resulting from the delayed apoptotic death of oligodendrocytes [99] .…”

Section: Sci Induces Death Of Neuronal and Glial Cells As Well As Inmentioning

confidence: 99%

“…Importantly, patients with SCI have increased oxidative stress for at least one year after the initial injury [94] . 95,96] . Furthermore, utilizing a mouse contusion model we recently showed that the induction of Nrf2 is sustained, lasting at least 42 days, and forms a delayed peak at 7 days after injury [97] .…”

Section: Sci Induces Death Of Neuronal and Glial Cells As Well As Inmentioning

confidence: 99%

“…Furthermore, Nrf2-deficient mice exhibit aggravated astrocyte activation [97] . Although increased astrogliosis may be induced by pro-inflammatory cytokines that are highly elevated in mice lacking Nrf2 [95,97] , activated astrocytes themselves can be a source of proinflammatory cytokines in the injured spinal cord [101] . Importantly, cultured Nrf2-deficient astrocytes have higher NF-κB binding activity and elevated levels of tumor necrosis factor (TNF), interleukin (IL)-1β, and IL-6 in response to scratch injury when compared with WT astrocytes [102] .…”

Section: Sci Induces Death Of Neuronal and Glial Cells As Well As Inmentioning

confidence: 99%

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Applications of the Keap1–Nrf2 system for gene and cell therapy

Pomeshchik

Leinonen

Malm

et al. 2015

Free Radical Biology and Medicine

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Effect of electroacupuncture on inhibition of inflammatory response and oxidative stress through activating ApoE and Nrf2 in a mouse model of spinal cord injury

et al. 2021

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Introduction: Electroacupuncture protects neurons and myelinated axons after spinal cord injury by mitigating the inflammatory response and oxidative stress, but how it exerts these effects is unclear.Methods and results: Spinal cord injury was induced in C57BL/6 wild-type and apolipoprotein E (ApoE) knockout (ApoE -/-) mice, followed by electroacupuncture or ApoE mimetic peptide COG112 treatment. Mice with spinal cord injury suffered loss of myelinated axons and hindlimb motor function through the detections of Basso mouse scale, histology, and transmission electron microscopy; electroacupuncture partially reversed these effects in wild-type mice but not in ApoE -/mice. Combining exogenous ApoE administration with electroacupuncture significantly mitigated the effects of spinal cord injury in both mouse strains, and these effects were associated with up-regulation of anti-inflammatory cytokines and down-regulation of proinflammatory cytokines which were detected by quantitative reverse transcriptionpolymerase chain reaction. Combination treatment also reduced oxidative stress by up-regulating ApoE and Nrf2/HO-1 signaling pathway through the detections of immunofluorescence and western blot analysis. Conclusions:These results suggest that electroacupuncture protects neurons and myelinated axons following spinal cord injury through an ApoE-dependent mechanism.

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Disruption of Nrf2 exacerbated the damage after spinal cord injury in mice

Abstract: Genetic ablation of Nrf2 exacerbated the neurologic deficit and inflammation after SCI in mice. These findings raise the possibility that Nrf2 could be relevant in improving outcome after SCI.

Cited by 39 publications

References 0 publications

Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Neuroprotective Effects of Sulforaphane after Contusive Spinal Cord Injury

Applications of the Keap1–Nrf2 system for gene and cell therapy

Effect of electroacupuncture on inhibition of inflammatory response and oxidative stress through activating ApoE and Nrf2 in a mouse model of spinal cord injury

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