See the published version of this preprint at Journal of Neuroinflammation.
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Wei Li
Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9258-3500
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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.
Keywords
Traumatic brain injury (TBI), Aubucin, Oxidative stress, Inflammation, Nuclear factor erythroid-2 related factor 2 (Nrf2)
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View the published article at Journal of Neuroinflammation.
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Received 01 Jun, 2020
Editorial decision: Accept
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Received 27 May, 2020
Reviewer #2 agreed
On 26 May, 2020
Reviewers invited
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Reviewer #1 agreed
On 23 May, 2020
Editor assigned
On 18 May, 2020
Submission checks complete
On 17 May, 2020
Editor invited
On 17 May, 2020
No comments provided
Review #1 received
Received 04 May, 2020
Editorial decision: Minor Revision
On 04 May, 2020
Review #3 received
Received 23 Apr, 2020
Review #2 received
Received 21 Apr, 2020
Reviewer #3 agreed
On 16 Apr, 2020
Reviewer #2 agreed
On 16 Apr, 2020
Reviewers invited
Invitations sent on 14 Apr, 2020
Reviewer #1 agreed
On 14 Apr, 2020
Editor invited
On 09 Apr, 2020
Editor assigned
On 08 Apr, 2020
Submission checks complete
On 07 Apr, 2020
No comments provided
Review #1 received
Received 09 Mar, 2020
Review #2 received
Received 09 Mar, 2020
Editorial decision: Major Revision
On 09 Mar, 2020
Review #3 received
Received 03 Mar, 2020
Reviewer #3 agreed
On 27 Feb, 2020
Reviewer #2 agreed
On 26 Feb, 2020
Editor invited
On 21 Feb, 2020
Reviewers invited
Invitations sent on 21 Feb, 2020
Reviewer #1 agreed
On 21 Feb, 2020
Editor assigned
On 20 Feb, 2020
First submitted
On 19 Feb, 2020
Submission checks complete
On 19 Feb, 2020
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See the published version of this preprint at Journal of Neuroinflammation.
This is a preprint, a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research
Wei Li
Nanjing University Medical School Affiliated Nanjing Drum Tower Hospital
Corresponding Author
ORCiD: https://orcid.org/0000-0002-9258-3500
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Published
View the published article at Journal of Neuroinflammation.
Version 3
Posted 27 May, 2020
No community comments so far
Review #1 received
Received 01 Jun, 2020
Editorial decision: Accept
On 01 Jun, 2020
Review #2 received
Received 27 May, 2020
Reviewer #2 agreed
On 26 May, 2020
Reviewers invited
Invitations sent on 23 May, 2020
Reviewer #1 agreed
On 23 May, 2020
Editor assigned
On 18 May, 2020
Submission checks complete
On 17 May, 2020
Editor invited
On 17 May, 2020
No comments provided
Review #1 received
Received 04 May, 2020
Editorial decision: Minor Revision
On 04 May, 2020
Review #3 received
Received 23 Apr, 2020
Review #2 received
Received 21 Apr, 2020
Reviewer #3 agreed
On 16 Apr, 2020
Reviewer #2 agreed
On 16 Apr, 2020
Reviewers invited
Invitations sent on 14 Apr, 2020
Reviewer #1 agreed
On 14 Apr, 2020
Editor invited
On 09 Apr, 2020
Editor assigned
On 08 Apr, 2020
Submission checks complete
On 07 Apr, 2020
No comments provided
Review #1 received
Received 09 Mar, 2020
Review #2 received
Received 09 Mar, 2020
Editorial decision: Major Revision
On 09 Mar, 2020
Review #3 received
Received 03 Mar, 2020
Reviewer #3 agreed
On 27 Feb, 2020
Reviewer #2 agreed
On 26 Feb, 2020
Editor invited
On 21 Feb, 2020
Reviewers invited
Invitations sent on 21 Feb, 2020
Reviewer #1 agreed
On 21 Feb, 2020
Editor assigned
On 20 Feb, 2020
First submitted
On 19 Feb, 2020
Submission checks complete
On 19 Feb, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
View the published article at Journal of Neuroinflammation.
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.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
This is a list of supplementary files associated with this preprint. Click to download.
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