Nuclear factor-κB and apoptosis in patients with intracerebral hemorrhage

Wang, Yaxian; Yan, Ai; Ma, Zhiyong; Wang, Zhuang; Zhang, Bing; Ping, Jinliang; Zhu, Jin-Shui; Zhou, Yue; Dai, Licheng

doi:10.1016/j.jocn.2010.11.039

Cited by 37 publications

(29 citation statements)

References 19 publications

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“…Necrosis and apoptosis are the major forms of pathologic cell death after ICH in animals and humans. 54–57 It was reported that the number of necrotic and apoptotic cells in the perihematomal area peaks at 72 h post-ICH. 57,58 This peak correlates with an increase in HMGB-1, which is released from necrotic cells and correlates positively with stroke severity.…”

Section: Discussionmentioning

confidence: 99%

(‐)‐Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways

Chang

Cho

Wang

2014

Ann Clin Transl Neurol

154

164

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Objective In the wake of intracerebral hemorrhage (ICH), a devastating stroke with no effective treatment, hemoglobin/iron-induced oxidative injury leads to neuronal loss and poor neurologic outcomes. (−)-Epicatechin (EC), a brain-permeable flavanol that modulates redox/oxidative stress via the NF-E2–related factor (Nrf) 2 pathway, has been shown to be beneficial for vascular and cognitive function in humans. Here, we examined whether EC can reduce early brain injury in ICH mouse models and investigated the underlying mechanisms. Methods ICH was induced by injecting collagenase, autologous blood, or thrombin into mouse striatum. EC was administered orally at 3 h after ICH and then every 24 h. Lesion volume, neurologic deficits, brain edema, reactive oxygen species, and protein expression and activity were evaluated. Results EC significantly reduced lesion volume and ameliorated neurologic deficits in both male and female ICH mice. Cell death and neuronal degeneration were decreased in the perihematomal area and were associated with reductions in caspase-3 activity and HMGB-1 level. These changes were accompanied by attenuation of oxidative insults, increased phase II enzyme expression, and increased Nrf2 nuclear accumulation. Interestingly, in addition to providing neuroprotection via Nrf2 signaling, EC diminished heme oxygenase-1 induction and brain iron deposition via an Nrf2-independent pathway that downregulated ICH-induced activating protein-1 activation and decreased matrix metalloproteinase 9 activity, lipocalin-2 levels, iron-dependent cell death, and ferroptosis-related gene expression. Interpretation Collectively, our data show that EC protects against ICH by activation of Nrf2-dependent and -independent pathways and may serve as a potential intervention for patients with ICH.

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Section: Discussionmentioning

confidence: 99%

(‐)‐Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways

Chang

Cho

Wang

2014

Ann Clin Transl Neurol

154

164

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“…In rodents (Wang et al, 2003; Wang and Tsirka, 2005b; Zhu et al, 2012) and humans (Wang et al, 2011), the major forms of cell death after ICH are necrosis and apoptosis. In the perihematomal region of rodents, the number of necrotic and apoptotic cells peaks at 72 h post-ICH (Matsushita et al, 2000; Zhu et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice

Xun

Chang

et al. 2015

Brain, Behavior, and Immunity

100

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Inflammatory mechanisms mediated by prostaglandins may contribute to the progression of intracerebral hemorrhage (ICH)-induced brain injury, but they are not fully understood. In this study, we examined the effect of prostaglandin E2 receptor EP1 (EP1R) activation and inhibition on brain injury in mouse models of ICH and investigated the underlying mechanism of action. ICH was induced by injecting collagenase, autologous blood, or thrombin into the striatum of middle-aged male and female mice and aged male mice. Effects of selective EP1R agonist ONO-DI-004, antagonist SC51089, and nonspecific Src family kinase inhibitor PP2 were evaluated by a combination of histologic, magnetic resonance imaging (MRI), immunofluorescence, molecular, cellular, and behavioral assessments. EP1R was expressed primarily in neurons and axons but not in astrocytes or microglia after ICH induced by collagenase. In middle-aged male mice subjected to collagenase-induced ICH, EP1R inhibition mitigated brain injury, brain edema, cell death, neuronal degeneration, neuroinflammation, and neurobehavioral deficits, whereas its activation exacerbated these outcomes. EP1R inhibition also was protective in middle-aged female mice and aged male mice after collagenase-induced ICH and in middle-aged male mice after blood- or thrombin-induced ICH. EP1R inhibition also reduced oxidative stress, white matter injury, and brain atrophy and improved functional outcomes. Histologic results were confirmed by MRI. Src kinase phosphorylation and matrix metalloproteinase-9 activity were increased by EP1R activation and decreased by EP1R inhibition. EP1R regulated matrix metalloproteinase-9 activity through Src kinase signaling, which mediated EP1R toxicity after collagenase-induced ICH. We conclude that prostaglandin E2 EP1R activation plays a toxic role after ICH through mechanisms that involve the Src kinases and the matrix metalloproteinase-9 signaling pathway. EP1R inhibition could be a novel therapeutic strategy to improve outcomes after ICH.

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“…The activity of NF-κB correlates with perilesional cell death after ICH in rats [58]. Activation of NF-κB is positively associated with the progression of apoptotic cell death in patients with ICH [59]. Therefore, understanding the signaling mechanisms underlying ICH-induced NF-κB activation may facilitate identification of therapeutic targets.…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury

Huang

Wang

Zhou

et al. 2013

J Neuroinflammation

171

119

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Intracerebral hemorrhage (ICH) is a common type of fatal stroke, accounting for about 15% to 20% of all strokes. Hemorrhagic strokes are associated with high mortality and morbidity, and increasing evidence shows that innate immune responses and inflammatory injury play a critical role in ICH-induced neurological deficits. However, the signaling pathways involved in ICH-induced inflammatory responses remain elusive. Toll-like receptor 4 (TLR4) belongs to a large family of pattern recognition receptors that play a key role in innate immunity and inflammatory responses. In this review, we summarize recent findings concerning the involvement of TLR4 signaling in ICH-induced inflammation and brain injury. We discuss the key mechanisms associated with TLR4 signaling in ICH and explore the potential for therapeutic intervention by targeting TLR4 signaling.

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Nuclear factor-κB and apoptosis in patients with intracerebral hemorrhage

Cited by 37 publications

References 19 publications

(‐)‐Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways

(‐)‐Epicatechin protects hemorrhagic brain via synergistic Nrf2 pathways

Toxic role of prostaglandin E2 receptor EP1 after intracerebral hemorrhage in mice

Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury

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