Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway

Wang, Junmin; Jiang, Chao; Zhang, Kun; Lan, Xi; Chen, Xuemei; Zang, Weidong; Wang, Zhongyu; Guan, Fangxia; Zhu, Changlian; Yang, Xiuli; Lü, Hong; Wang, Jian

doi:10.1016/j.freeradbiomed.2018.12.014

Cited by 133 publications

(111 citation statements)

References 60 publications

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“…We hypothesize that attenuation of oxidative stress reduces the release of HMGB1, which alleviates the in ammatory response. Similarly, Zeng and Wang have reported that elevated antioxidant response reduces the in ammation and weakens the brain damage in the TBI model [10,12].…”

Section: Discussionmentioning

confidence: 80%

“…Secondary brain injury has complex and varied pathophysiological mechanisms. Substantial evidence suggests that oxidative stress participates in secondary brain injury [4,10,11,17]. Recently, studies have demonstrated that Au has potent antioxidant effects and reduces excessive production of ROS in nonalcoholic fatty liver disease and acute lung injury [37,38].…”

Section: Discussionmentioning

confidence: 99%

“…ATP, RNA, high mobility group box-1) to initiate or exacerbate neuroin ammation, which can also further promote ROS generation [8,9]. Extensive animal data suggest that elevated antioxidant response and reduced in ammation would attenuate brain damage [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

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Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Wang

Zhou²,

et al. 2020

Preprint

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Background: Aucubin (Au), an iridoid glycoside from natural plants, has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H 2 O 2 -induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model. Methods: In vitro experiments, the various concentrations of Au (50 μg/ml, 100 μg/ml or 200 μg/ml) were added in culture medium at 0h and 6h after neurons stimulated by H 2 O 2 (100μM). After exposed for 12 hours, neurons were collected for western blot (WB), immunofluorescence and M29,79-dichlorodihydrofluorescein diacetate (DCFH-DA) staining. In vivo experiments, Au (20 mg/kg or 40 mg/kg) was administrated intraperitoneally at 30 min, 12 h, 24 h, and 48 h after modeling. Brain water content, neurological deficits and cognitive functions were measured at specific time, respectively. Cortical tissue around focal trauma was collected for WB, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA) at 72 h after TBI. RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with Au (40 mg/kg) treatment. Mice were intracerebroventricularly administrated with lentivirus at 72 h before TBI establishment. The cortex was obtained at 72 h after TBI and used for WB and q-PCR. Results: Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis both in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au. Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system.

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

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Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Wang

Zhou²,

et al. 2020

Preprint

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“…Our study has the limitation that data on other compounds of oxidant and antioxidant states were not reported. However, we believe that the results of our study and the beneficial effects found with the antioxidant agents administration in TBI animal models (reducing oxidative status and neurological deficits) [18][19][20][21][22][23][24][25] could motivate the research on TAC in TBI patients. We believe that validating the role of serum TAC concentrations at any time during the first week of TBI could be interesting in the prediction of mortality in TBI patients because it could help clinicians in prognosticating these patients.…”

Section: Discussionmentioning

confidence: 99%

Traumatic Brain Injury Patients Mortality and Serum Total Antioxidant Capacity

et al. 2020

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Objective: Oxidation is involved in secondary brain injury after traumatic brain injury (TBI). Increased concentrations of total antioxidant capacity (TAC) in blood at the time of admission for TBI have been found in non-surviving patients. The main objective of this study was to determine the role of serum TAC levels at any time during the first week of TBI for the prediction of early mortality. Methods: Isolated (<10 points in non-cranial aspects of Injury Severity Score) and severe (<9 points in Glasgow Coma Scale) TBI patients were included. Serum TAC concentrations at days 1, 4, and 8 of TBI were determined. The end-point study was 30-day mortality. Results: Higher serum TAC levels at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p = 0.002) of TBI were found in non-surviving (n = 34) than in surviving patients (n = 90). The area under curve (95% Confidence Interval) for prediction of 30-day mortality by serum TAC concentrations at days 1, 4, and 8 of TBI were 0.79 (0.71-0.86; p < 0.001), 0.87 (0.79-0.93; p < 0.001), and 0.76 (0.67-0.84; p = 0.006) respectively. Conclusions: The novelty of our study was the ability to predict 30-day mortality by serum TAC concentrations at any time during the first week of TBI.

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“…ATP, RNA, high mobility group box-1) to initiate or exacerbate neuroinflammation, which can also further promote ROS generation [8,9]. Extensive animal data suggest that elevated antioxidant response and reduced inflammation would attenuate brain damage [10][11][12].Nuclear factor erythroid-2 related factor 2 (Nrf2) has considerable neuroprotective effects in central nervous system (CNS) diseases[13-15]. Nrf2 is a transcription factor that takes part in regulation of cellular response to oxidative stress.…”

mentioning

confidence: 99%

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Wang

Zhou²,

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Aucubin (Au) has anti-oxidative and anti-inflammatory bioactivities; however, its effects on a traumatic brain injury (TBI) model remain unknown. We explored the potential role of Au in a H 2 O 2 -induced oxidant damage in primary cortical neurons and weight-drop induced-TBI in a mouse model.Methods: Neuronal apoptosis, brain water content, histological damages and neurological deficits and cognitive functions were measured. We performed western blot, TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, Nissl staining, quantitative real time polymerase chain reaction (q-PCR), immunofluorescence/immunohistochemistry and enzyme linked immunosorbent assay (ELISA). RNA interference experiments were performed to determine the effects of Nuclear factor erythroid-2 related factor 2 (Nrf2) on TBI mice with intraperitoneal injection of Au.Results: We found that Au enhanced the translocation of Nrf2 into the nucleus, activated antioxidant enzymes, suppressed excessive generation of reactive oxygen species (ROS) and reduced cell apoptosis in vitro and vivo experiments. In the mice model of TBI, Au markedly attenuated brain edema, histological damages and improved neurological and cognitive deficits. Au significantly suppressed high mobility group box 1(HMGB1)-mediated aseptic inflammation. Nrf2 knockdown in TBI mice blunted the antioxidant and anti-inflammatory neuroprotective effects of the Au.Conclusions: Taken together, our data suggest that Au provides a neuroprotective effect in TBI mice model by inhibiting oxidative stress and inflammatory responses; the mechanisms involve triggering Nrf2-induced antioxidant system. pathobiological features of secondary brain damage [4,5]. Excessive production of free radicals leads to lipid peroxidation, protein degradation, and genotoxicity leading to cellular and tissue damage [6].The brain is an organ with a high content of polyunsaturated fatty acids, which also makes it vulnerable to free radical attack and lipid peroxidation [7]. In addition, OS damage to mitochondrial function can collapse the cellular bioenergetics leading to cell apoptosis [6]. These OS-induced damaged cells releases damage associated molecular patterns (DAMPs; e.g. ATP, RNA, high mobility group box-1) to initiate or exacerbate neuroinflammation, which can also further promote ROS generation [8,9]. Extensive animal data suggest that elevated antioxidant response and reduced inflammation would attenuate brain damage [10][11][12].Nuclear factor erythroid-2 related factor 2 (Nrf2) has considerable neuroprotective effects in central nervous system (CNS) diseases[13-15]. Nrf2 is a transcription factor that takes part in regulation of cellular response to oxidative stress. Under normal physiological conditions, Kelch-like ECH-associated protein 1 (Keap1) combines with Nrf2 and enhances Nrf2 degradation. Once stimulated, Nrf2 translocates into the nucleus and binds to the antioxidant response element (ARE) in the promoter of antioxidant genes, thereby inducing the expression of antioxidant and detoxifi...

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Melatonin receptor activation provides cerebral protection after traumatic brain injury by mitigating oxidative stress and inflammation via the Nrf2 signaling pathway

Cited by 133 publications

References 60 publications

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

Traumatic Brain Injury Patients Mortality and Serum Total Antioxidant Capacity

Aucubin alleviates oxidative stress and inflammation via Nrf2-mediated signaling activity in experimental traumatic brain injury

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