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Sinomenine Reduces Neuronal Cell Apoptosis in Mice After Traumatic Brain Injury via Its Effect on Mitochondrial Pathway

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Sinomenine Reduces Neuronal Cell Apoptosis in Mice After Traumatic Brain Injury via Its Effect on Mitochondrial Pathway

Chuanjing Fu et al. Drug Des Devel Ther.

Abstract

Background: Sinomenine (SIN) has been shown to have protective effects against brain damage following traumatic brain injury (TBI). However, the mechanisms and its role in these effects remain unclear. This study was conducted to investigate the potential mechanisms of the protective effects of SIN.

Methods: The weight-drop model of TBI in Institute of Cancer Research (ICR) mice were treated with SIN or a vehicle via intraperitoneal administration 30 min after TBI. All mice were euthanized 24 h after TBI and after neurological scoring, a series of tests were performed, including brain water content and neuronal cell death in the cerebral cortex.

Results: The level of cytochrome c (Cyt c), malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase 1 (SOD) were restored to some degree following the SIN treatment. The SIN treatment significantly decreased caspase-3 expression and reduced the number of positive cells by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and improved the survival of neuronal cells. Additionally, the pretreatment levels of MDA were restored, while Bax translocation to mitochondria and Cyt c release into the cytosol were reduced by the SIN treatment.

Conclusion: SIN protected neuronal cells by protecting them against apoptosis via mechanisms that involve the mitochondria following TBI.

Keywords: apoptosis; mitochondria; sinomenine; traumatic brain injury.

Conflict of interest statement

Disclosure The authors report no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Administration of SIN protects rats against secondary brain injury after TBI. Notes: (A and B) The grip test score was performed while brain water content was examined at 1 day after TBI. Brain water content was significantly lower in the groups administered SIN (10, 30, and 70 mg/kg) than in the group receiving vehicle. Data are presented as the mean ± SEM; **P<0.01, ***P<0.001 vs sham group; #P<0.05 vs TBI + vehicle group. Abbreviations: SIN, sinomenine; TBI, traumatic brain injury.
Figure 2
Figure 2
SIN suppresses neural apoptosis induced by TBI. Notes: (AE) Nissl staining of cortical tissue sections shows neuronal damage in mice subjected to TBI, which was alleviated by SIN treatment (30 mg/kg) (arrows in BD). Data are presented as the mean ± SEM. **P<0.01 vs sham group; #P<0.05 vs TBI + vehicle group. Abbreviations: SIN, sinomenine; TBI, traumatic brain injury.
Figure 3
Figure 3
The representative photomicrographs showing caspase-3 immunohistochemistry of the tissue samples from different groups 1 day after TBI. Notes: Caspase-3 immunohistochemistry of tissue from different group 1 day after TBI (AD, F). The effect of SIN on cleaved caspase-3 expression in cortical neural cells in a mice model of TBI was assessed by Western blot analysis (E and G). Data are presented as the mean ± SEM. **P<0.01 vs sham group; #P<0.05 vs TBI + vehicle group. Abbreviations: SIN, sinomenine; TBI, traumatic brain injury.
Figure 4
Figure 4
Effect of SIN on proapoptotic protein expression was assessed following TBI. Notes: The expression of Bcl-2, Bax, and Cyt c in the ipsilateral cortex was evaluated by Western blotting 24 h after injury (A and B). Representative blots show the relative expression of mitochondrial cytosolic Cyt c (C and D), Bax (E and F), and Bcl-2 (G and H). Expression was normalized to the level of COX IV or β-actin. Data represent as mean ± SEM. *P<0.05, **P<0.01, ***P<0.001 vs sham group; #P<0.05, ##P<0.01 vs TBI + vehicle group. Abbreviations: Cyt c, cytochrome c; SIN, sinomenine; mit, mitochondria; TBI, traumatic brain injury.
Figure 5
Figure 5
SIN attenuated mitochondrial oxidative stress caused by TBI. Notes: (A) Measurements of MDA levels. (B) The activity of SOD. (C) The activity of GPx. Data represented as mean ± SEM. **P<0.01, ***P<0.001 vs sham group; #P<0.05, ###P<0.001 vs TBI + vehicle group. Abbreviations: GPx, glutathione peroxidase; MDA, malondialdehyde; SIN, sinomenine; SOD, superoxide dismutase; TBI, traumatic brain injury.

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