BpV(pic) confers neuroprotection by inhibiting M1 microglial polarization and MCP-1 expression in rat traumatic brain injury
Introduction
Traumatic brain injury (TBI) is a leading cause of mortality and morbidity worldwide with few effective treatment options (Xiong et al., 2010). Approximately 10 million deaths per year and/or hospitalization are directly related to traumatic brain injury. Current treatment strategies rely on acute therapeutic intervention to reduce cell damage and brain edema (Narayan et al., 2002). Although we have a broad understanding of TBI, there has been no effective neuroprotective treatment to promote functional recovery after TBI. The inflammatory response is thought to be a key factor in the cascade of secondary injury after TBI. TBI induces a strong inflammatory response characterized by recruitment of peripheral leukocytes into brain parenchyma and activation of resident immune cells (Rhodes, 2011). TBI-induced microglial activation and subsequent release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukins (IL), can lead to direct neuronal apoptosis(Guadagno et al., 2015). Moreover, these pro-inflammatory cytokines stimulate nitric oxide synthesis, leading to increased brain edema, brain damage, and further promote neuronal apoptosis(Corrigan et al., 2016; Guadagno et al., 2015).
Bisperoxovanadium (pyridine-2-carboxyl) [bpV(pic)] is an inhibitor of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) (Liu et al., 2017). PTEN is a tumor suppressor, which plays an important role in intracellular signal transduction that mediates cell proliferation and survival (Wang et al., 2015). PTEN has two activities of lipid phosphatase and protein phosphatase (Poon et al., 2010). The function of bpV(pic) is to inhibit PTEN lipid phosphatase activity (Chen et al., 2015). PTEN lipid phosphatase activity is always associated with AKT activation, during inhibition of the lipid phosphatase activity of PTEN. AKT activation exhibits neuroprotection in many neuropathological conditions (Makker et al., 2014). Previous studies have demonstrated that neuronal AKT can be activated by bpV(pic) to reduce neuronal death in ischemic stroke injury (Shi et al., 2011). Althrough the neuroprotective effect of bpV(pic) has been extensively studied, its’ role in TBI remains larger unclear.
In this study, our results indicate that bpV(pic) exhibits neuroprotection in rat TBI through AKT activation. We show that bpV(pic) inhibits M1 microglial polarization after TBI by activation of AKT and subsequent inhibition of NF-κB p65. BpV(pic) also suppresses the expression of MCP-1 by regulating the AKT/NF-κB p65 signaling pathway, thereby attenuating inflammation.
Section snippets
Animals
Adult male Sprague-Dawley (SD) rats were given free water and food in a temperature-controlled room (23–25 °C) with 12-hour light/dark cycle, 3 mice per cage. Animals were allowed to adapt to the environment for at least 3 days before the experiment. In our in vivo experiments, we used a total of 324 male rats and discarded 23 male rats during surgery. 9 adult pregnant female rats and 46 embryos were used in our cortical microglia culture experiments. All animal use and experimental protocols
BpV(pic) treatment reduces brain water content and promotes functional recovery after TBI
Traumatic brain injury is defined as brain damage caused by external mechanical forces, including acceleration, deceleration, and rotational forces. To inverstigate the potential neuroprotective effects of bpV(pic) on TBI, we used a modified Feeney’s weigh-drop method to induce experimental TBI model in rats. As shown in Fig. 1a, the percentage of water content of rat brain was significantly increased after 72 h of TBI, and this was partly prevented by bpV(pic) treatment. In addition, to assess
Discussion
PTEN is a tumor supressor and plays an important role in mediating intracellular signaling of cell proliferation and survival (Milella et al., 2015; Muniyan et al., 2014). Previous studies from us and others have shown that inhibition of PTEN confers neuroprotective effect in ischemic stroke injury (Chen et al., 2016; Zhang et al., 2017). BpV(pic) is a commercially available PTEN inhibitor. We have widely known that bpV(pic) plays a neuroprotective role in the activation of AKT by inhibiting
Author disclosure
We confirm that there are no conflicts of interest associated with this publication.
Acknowledgements
This work was supported by China Key Project of Basic Research (“973″ Project; 2014CB541606), Natural Science Foundation of China (NSFC; 81470599) and The Fund of Collaborative Innovation Center for Brain Science to Q.W.
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