Abstract
The neuroprotective effect of sinomenine (SIN) has been demonstrated in several brain injury models. However, its role and molecular mechanism in traumatic brain injury (TBI) remain unknown. In this study, we investigated the neuroprotective effects of SIN in the weight-drop model of TBI in male ICR mice. Mice were randomly divided into the sham and TBI groups, SIN (10 mg/kg, 30 mg/kg and 50 mg/kg, administered intraperitoneally) or equal volume of vehicle was given at 30 min after TBI. Treatment with 30 mg/kg SIN significantly improved motor performance and alleviated cerebral edema. However, treatment with 10 mg/kg or 50 mg/kg SIN did not exhibit a better outcome. Therefore, we chose 30 mg/kg SIN for our subsequent experiments. SIN significantly increased the expression of Bcl-2 and decreased that of cleaved caspase-3, indicating that SIN is anti-apoptotic. This was confirmed by the observation that SIN-treated animals had fewer apoptotic neurons. Cortical malondialdehyde content, glutathione peroxidase (GPx) activity and superoxide dismutase (SOD) activity were restored in the group that received SIN. Furthermore, Western blot and immunofluorescence experiments showed that SIN enhanced the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus. SIN administration also significantly upregulated the expression of the downstream factors heme oxygenase 1 and NAD(P)H:quinone oxidoreductase 1 at pre- and post-transcriptional levels. Together, these data demonstrate that SIN exerts a neuroprotective effect in a model of TBI, possibly by activating the Nrf2–antioxidant response element (ARE) pathway.
Highlights
Traumatic brain injury (TBI) remains a major public health problem in modern society, leading to high medical costs, morbidity and mortality (Zipper and Mulcahy, 2003; Tsai et al, 2013)
The sham group showed no difference between different time points and there was no difference between the TBI group and the vehicle-treated group
Within 3 days after TBI, the performance of the groups that received SIN was significantly better than those that received vehicle
Summary
Traumatic brain injury (TBI) remains a major public health problem in modern society, leading to high medical costs, morbidity and mortality (Zipper and Mulcahy, 2003; Tsai et al, 2013). After a primary brain insult, a complex series of endogenous events are triggered, including oxidative stress, glutamate excitotoxicity, activation of the inflammatory response, loss of ionic homeostasis, and increased vascular permeability (Werner and Engelhard, 2007; Bell et al, 2009; Cornelius et al, 2013), leading to further neuronal degeneration and apoptosis. These subsequent pathological events are referred to as secondary brain injury. The excessive production of ROS damages cellular components including lipids, proteins, and DNA, leading to a decline in physiological function and cell death (Ansari et al, 2008; Adibhatla and Hatcher, 2010)
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