Transcription Factor Nrf2 Protects the Brain From Damage Produced by Intracerebral Hemorrhage

Zhao, Xiurong; Sun, Guanghua; Zhang, Jie; Strong, Roger; Dash, Pramod K.; Kan, Yuet Wai; Grotta, James C.; Aronowski, Jaroslaw

doi:10.1161/strokeaha.107.486506

Cited by 209 publications

(216 citation statements)

References 50 publications

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“…For example, systemic administration of sulforaphane reduced LPS-induced inflammation in the brain (13). In an intracerebral hemorrhage model, sulforaphane reduced oxidative stress-induced brain damage by activating Nrf2 signaling (23). In this study, we found that sulforaphane has strong analgesic effects on SNT-induced pain hypersensitivity, suggesting additional therapeutic potential for this molecule in the treatment of neuropathic pain.…”

Section: Discussionsupporting

confidence: 49%

NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

Kim

You

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

214

198

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Increasing evidence supports the notion that spinal cord microglia activation plays a causal role in the development of neuropathic pain after peripheral nerve injury; yet the mechanisms for microglia activation remain elusive. Here, we provide evidence that NADPH oxidase 2 (Nox2)-derived ROS production plays a critical role in nerve injury-induced spinal cord microglia activation and subsequent pain hypersensitivity. Nox2 expression was induced in dorsal horn microglia immediately after L5 spinal nerve transection (SNT). Studies using Nox2-deficient mice show that Nox2 is required for SNT-induced ROS generation, microglia activation, and proinflammatory cytokine expression in the spinal cord. SNT-induced mechanical allodynia and thermal hyperalgesia were similarly attenuated in Nox2-deficient mice. In addition, reducing microglial ROS level via intrathecal sulforaphane administration attenuated mechanical allodynia and thermal hyperalgesia in SNT-injured mice. Sulforaphane also inhibited SNT-induced proinflammatory gene expression in microglia, and studies using primary microglia indicate that ROS generation is required for proinflammatory gene expression in microglia. These studies delineate a pathway involving nerve damage leading to microglial Nox2-generated ROS, resulting in the expression of proinflammatory cytokines that are involved in the initiation of neuropathic pain.spinal nerve transection | sulforaphane D amage to the peripheral nerve often results in abnormal chronic pain and pain hypersensitivity that are generally referred to as "neuropathic pain." It is known that hypersensitivity of pain-transmission neurons in the spinal cord is involved in the development of neuropathic pain, and this process has been referred to as central sensitization (1). Various pathological events are reported to precede central sensitization. These include, but are not limited to, p38 activation in spinal cord microglia and subsequent proinflammatory cytokine expression, NMDA receptor phosphorylation in spinal cord neurons, and altered expression of ion channels on neurons (2-5). In addition, a series of studies have implied that production of reactive oxygen species (ROS) in the spinal cord is involved in the induction of neuropathic pain. For example, systemic injection of ROS scavengers, such as phenyl-N-tert-butylnitrone (PBN) and 5,5-dimethylpyrroline-N-oxide (DMPO), relieved spinal nerve ligation-induced pain hypersensitivity in rats (6). In addition, spinal nerve ligation-induced phosphorylation of the NMDA receptor subunit 1 (NR1) in dorsal horn neurons was attenuated by ROS scavengers (7). These results suggested that ROS are critically involved in the development and maintenance of neuropathic pain; however, the exact primary source of ROS production has remained elusive.Recently, a study using the mitochondrial ROS detector MT-Red showed that ROS are generated in the mitochondria of dorsal horn neurons (8). Production of mitochondrial ROS by intrathecal injection of the electron transport complex inhibitors...

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Section: Discussionsupporting

confidence: 49%

NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

Kim

You

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

214

198

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“…The former is known as intracerebral haemorrhage (ICH) and the latter condition is known as subarachnoid haemorrhage (SAH) (Feigin et al 2005). Reports using ICH models have shown that Nrf2 subjected to both pre-treatment and post-treatment are significantly effective in expressing Nrf2-dependent cytoprotective proteins, which subsequently cause a reduction in oxidative burden to brain tissue and, thus, increase the recovery of neurological function (Zhao et al 2007). It has been reported that, using SAH rat models, the Nrf2-ARE pathway is activated in the cortex during an early stage of SAH.…”

Section: Ischaemia and Strokementioning

confidence: 99%

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

et al. 2016

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The overproduction of reactive oxygen species (ROS) generates oxidative stress in cells. Oxidative stress results in various pathophysiological conditions, especially cancers and neurodegenerative diseases (NDD). The Keap1-Nrf2 [Kelch-like ECH-associated protein 1-nuclear factor (erythroid-derived 2)-like 2] regulatory pathway plays a central role in protecting cells against oxidative and xenobiotic stresses. The Nrf2 transcription factor activates the transcription of several cytoprotective genes that have been implicated in protection from cancer and NDD. The Keap1-Nrf2 system acts as a double-edged sword: Nrf2 activity protects cells and makes the cell resistant to oxidative and electrophilic stresses, whereas elevated Nrf2 activity helps in cancer cell survival and proliferation. Several groups in the recent past, from both academics and industry, have reported the potential role of Nrf2-mediated transcription to protect from cancer and NDD, resulting from mechanisms involving xenobiotic and oxidative stress. It suggests that the Keap1-Nrf2 system is a potential therapeutic target to combat cancer and NDD by designing and developing modulators (inhibitors/activators) for Nrf2 activation. Herein, we review and discuss the recent advancement in the regulation of the Keap1-Nrf2 system, its role under physiological and pathophysiological conditions including cancer and NDD, and modulators design strategies for Nrf2 activation.

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“…Moreover, overexpression of Nrf2 protects cells from Fas-induced apoptosis suggesting an important role of Nrf2 in anti-apoptotic pathways (Kotlo et al, 2003). Activation of the Nrf2/ARE pathway has been shown to be neuroprotective following several types of acute insults to the central nervous system (CNS), such as intracerebral hemorrhage (Wang et al, 2007;Zhao et al, 2007bZhao et al, , 2009, focal cerebral ischemia (Zhao et al, 2006) and traumatic brain injury (TBI) ( Jin et al, 2009;Yan et al, 2008;Zhao et al, 2007a). Collectively, these observations suggest that Nrf2/ARE signaling plays an important role in cellular survival by modulating both cellular antioxidant potential and apoptosis pathway.…”

Section: Figmentioning

confidence: 99%

Activation of the Nuclear Factor E2-Related Factor 2/Antioxidant Response Element Pathway Is Neuroprotective after Spinal Cord Injury

Wang

Vaccari

Wang

et al. 2012

Journal of Neurotrauma

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The activation of oxidative damage, neuroinflammation, and mitochondrial dysfunction has been implicated in secondary pathomechanisms following spinal cord injury (SCI). These pathophysiological processes lead to cell death and are tightly regulated by nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling. Here, we investigated whether activation of Nrf2/ARE is neuroprotective following SCI. Female Fischer rats were subjected to mild thoracic SCI (T8) using the New York University injury device. As early as 30 min after SCI, levels of Nrf2 transcription factor were increased in both nuclear and cytoplasmic fractions of neurons and astrocytes at the lesion site and remained elevated for 3 days. Treatment of injured rats with sulforaphane, an activator of Nrf2/ARE signaling, significantly increased levels of Nrf2 and glutamate-cysteine ligase (GCL), a rate-limiting enzyme for synthesis of glutathione, and decreased levels of inflammatory cytokines, interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) thus leading to a reduction in contusion volume and improvement in coordination. These results show that activation of the Nrf2/ARE pathway following SCI is neuroprotective and that sulforaphane is a viable compound for neurotherapeutic intervention in blocking pathomechanisms following SCI.

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Transcription Factor Nrf2 Protects the Brain From Damage Produced by Intracerebral Hemorrhage

Cited by 209 publications

References 50 publications

NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

NADPH oxidase 2-derived reactive oxygen species in spinal cord microglia contribute to peripheral nerve injury-induced neuropathic pain

The Keap1–Nrf2 pathway: promising therapeutic target to counteract ROS-mediated damage in cancers and neurodegenerative diseases

Activation of the Nuclear Factor E2-Related Factor 2/Antioxidant Response Element Pathway Is Neuroprotective after Spinal Cord Injury

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