Neuroprotective effects of ebselen in traumatic brain injury model: involvement of nitric oxide and p38 mitogen‐activated protein kinase signalling pathway

Liang, Wei; Zhang, Yanfei; Yang, Cheng; Wang, Qi; Zhuang, Zhongwei; Sun, Zhiyang

doi:10.1111/1440-1681.12186

Cited by 24 publications

(14 citation statements)

References 35 publications

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“…Our results were consistent with a previous study [27]. Unlike our study, Wei et al demonstrated that both a 10 mg/kg and a 30 mg/kg dose of ebselen administered by an intragastric route significantly reduced the NO and iNOS mRNA levels in rats with a traumatic brain injury model in a dose-dependent manner [28]. In our study, a 30 mg/kg dose of ebselen did not reduce NO levels or the number of iNOS positive cells.…”

Section: Discussionsupporting

confidence: 93%

Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

et al. 2015

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Ebselen is an organoselenium compound which has strong antioxidant and anti-inflammatory effects. We investigated the neuroprotective role of ebselen pretreatment in rats with experimental sciatic nerve ischemia-reperfusion (I/R) injury. Adult male Sprague Dawley rats were divided into four groups (N = 7 in each group). Before sciatic nerve I/R was induced, ebselen was injected intraperitoneally at doses of 15 and 30 mg/kg. After a 2 h ischemia and a 3 h reperfusion period, sciatic nerve tissues were excised. Tissue levels of malondialdehyde (MDA) and nitric oxide (NO), and activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) were measured. Sciatic nerve tissues were also examined histopathologically. The 15 mg/kg dose of ebselen reduced sciatic nerve damage and apoptosis (P < 0.01), levels of MDA, NO, and inducible nitric oxide synthase (iNOS) positive cells (P < 0.01, P < 0.05, respectively), and increased SOD, GPx, and CAT activities (P < 0.001, P < 0.01, P < 0.05, respectively) compared with the I/R group that did not receive ebselen. Conversely, the 30 mg/kg dose of ebselen increased sciatic nerve damage, apoptosis, iNOS positive cells (P < 0.01, P < 0.05, P < 0.001) and MDA and NO levels (P < 0.05, P < 0.01) and decreased SOD, GPx, and CAT activities (P < 0.05) compared with the sham group. The results of this study suggest that ebselen may cause different effects depending on the dose employed. Ebselen may be protective against sciatic nerve I/R injury via antioxidant and antiapoptotic activities at a 15 mg/kg dose, conversely higher doses may cause detrimental effects.

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Section: Discussionsupporting

confidence: 93%

Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

et al. 2015

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“…Activation of p38 leads to the production of cleaved caspase-3 and a reduction in bcl-2, thus resulting in apoptotic neuronal death ( Raghupathi et al, 2003 ). Previous studies have shown significant activation of p38 in the brain after TBI ( Tang et al, 2012 ; Wei et al, 2014 ; Li et al, 2017 ; Yang et al, 2017 ). Blocking p38 activation attenuates matrix metalloprotein-9 (MMP-9) expression and thus mitigates brain edema following TBI ( Tang et al, 2012 ).…”

Section: Discussionmentioning

confidence: 86%

LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats

Qin

Gao

et al. 2018

Front. Cell. Neurosci.

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Leucine-rich repeat kinase 2 (LRRK2) is widely expressed in the brain and exerts neurotoxicity in Parkinson’s disease. The p38/Drosha signaling activation has been reported to increase cell death under stress. This study was designed to investigate the potential role and mechanism of LRRK2 in secondary brain injury after traumatic brain injury (TBI). A total of 130 male Sprague-Dawley rats were examined using a weight-drop model of TBI. The rats received the specific LRRK2 inhibitor PF-06447475 or LRRK2 pDNA alone or in combination with Drosha pDNA. Real-time PCR, western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses were conducted. Our results showed that after TBI, endogenous LRRK2 expression and p38 phosphorylation were increased, whereas Drosha expression was inhibited. Administration of the LRRK2 inhibitor PF-06447475 significantly reduced neuronal apoptosis, brain water content, and blood–brain barrier permeability 12 h after TBI and ameliorated neurological deficits 72 h after TBI, which was concomitant with decreased p38 phosphorylation and increased Drosha expression. Conversely, LRRK2 overexpression induced the opposite effect. Moreover, the neurotoxic effects of LRRK2 on TBI were also eliminated by Drosha overexpression. Altogether, these findings demonstrate the importance of TBI-induced LRRK2 upregulation during the induction of post-traumatic neurological injury, which may be partially mediated through a p38/Drosha signaling pathway.

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“…Following bilateral entorhinal cortex lesion, GPx4 expression is upregulated in reactive astrocytes of lesioned areas but not in neurons. The GPx mimic, Ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one], is reported to reduce NO levels and modulate the TL4-mediated p38-MAPK pathway after weight drop injury in rats (Wei et al, 2014). …”

Section: Therapeutic Strategies Targeting Lipid Peroxidationmentioning

confidence: 99%

Therapies targeting lipid peroxidation in traumatic brain injury

2016

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Lipid peroxidation can be broadly defined as the process of inserting a hydroperoxy group into a lipid. Polyunsaturated fatty acids present in the phospholipids are often the targets for peroxidation. Phospholipids are indispensable for normal structure of membranes. The other important function of phospholipids stems from their role as a source of lipid mediators – oxygenated free fatty acids that are derived from lipid peroxidation. In the CNS, excessive accumulation of either oxidized phospholipids or oxygenated free fatty acids may be associated with damage occurring during acute brain injury and subsequent inflammatory responses. There is a growing body of evidence that lipid peroxidation occurs after severe traumatic brain injury in humans and correlates with the injury severity and mortality. Identification of the products and sources of lipid peroxidation and its enzymatic or non-enzymatic nature is essential for the design of mechanism-based therapies. Recent progress in mass spectrometry-based lipidomics/oxidative lipidomics offers remarkable opportunities for quantitative characterization of lipid peroxidation products, providing guidance for targeted development of specific therapeutic modalities. In this review, we critically evaluate previous attempts to use non-specific antioxidants as neuroprotectors and emphasize new approaches based on recent breakthroughs in understanding of enzymatic mechanisms of lipid peroxidation associated with specific death pathways, particularly apoptosis. We also emphasize the role of different phospholipases (calcium-dependent and -independent) in hydrolysis of peroxidized phospholipids and generation of pro- and anti-inflammatory lipid mediators.

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Neuroprotective effects of ebselen in traumatic brain injury model: involvement of nitric oxide and p38 mitogen‐activated protein kinase signalling pathway

Cited by 24 publications

References 35 publications

Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

Different dose-dependent effects of ebselen in sciatic nerve ischemia-reperfusion injury in rats

LRRK2 Contributes to Secondary Brain Injury Through a p38/Drosha Signaling Pathway After Traumatic Brain Injury in Rats

Therapies targeting lipid peroxidation in traumatic brain injury

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