Traumatic Brain Injury-Induced Neuronal Apoptosis is Reduced Through Modulation of PI3K and Autophagy Pathways in Mouse by FTY720

Abstract

FTY720 is a synthetic compound produced by modification of metabolite from Isaria sinclairii. It is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues, thereby causing peripheral lymphopenia. Growing evidences have suggested that apoptosis and autophagy were involved in the secondary brain injury after traumatic brain injury (TBI) although FTY720 exerted neuroprotective effects in a variety of neurological diseases except TBI. The present study was aimed to investigate the role of FTY720 in a mouse model of TBI. In experiment 1, ICR mice were divided into four groups: sham group, TBI group, TBI + vehicle group, and TBI + FTY720 group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 administration after TBI improved neurobehavioral function, alleviated brain edema, accompanied by modulation of apoptotic indicators such as Bcl-2, Bcl-xL, Bax, and cytochrome c. In experiment 2, ICR mice were also divided into four groups: sham group, TBI + vehicle group, TBI + FTY720 group, and TBI + FTY720 + inhibitors group. And the injured cerebral cortex (including both contused and penumbra) was used for analysis. We found that FTY720 increased the expression of phospho-protein kinase B (AKT) and some autophagy markers such as LC3 and Beclin 1. In addition, the apoptosis inhibition effect of FTY720 was partly abrogated by the phosphatidylinositide 3-kinases (PI3K)/AKT pathway inhibitor LY294002 and autophagy inhibitor 3-methyladenine. Collectively, our data provide the first evidence that FTY720 exerted neuroprotective effects after TBI, at least in part, through the activation of PI3K/AKT pathway and autophagy.

Fucoxanthin provides neuroprotection in models of traumatic brain injury via the Nrf2-ARE and Nrf2-autophagy pathways

“…The in vivo model of TBI employed in the present study was based on a weight-drop model described previously36. In brief, mice were anesthetized with chloral hydrate (1%, 5 ml/kg) intraperitoneal (i.p.)…”

“…The scoring system was adapted from previously published methods39. A detailed description of our NSS testing procedure and the contribution of individual tasks to the composite NSS was published previously36. For grip test, mice were placed on a thin, horizontal, metal 45 cm long wire which was lay up between two vertical poles 45 cm above a foam pad.…”

A Three-Day Consecutive Fingolimod Administration Improves Neurological Functions and Modulates Multiple Immune Responses of CCI Mice

“…Fingolimod reduces the accumulation of monocytes and IL-16 after TBI [20,21]. However, whether the administration of fingolimod can improve the functional outcome is still controversial [22,23]. A previous study demonstrated the reduction of neuroinflammation but no functional improvement with a single-dose administration of 1 mg/kg fingolimod before TBI [22].…”

“…Therefore, the 3-day therapy is chosen in this article. By reference to previous studies [21][22][23], the dose of 1 mg/kg is used in this study, which is approximately 10 times the FDA-approved dose of 0.5 mg/ day in humans on a milligram/square meter basis.…”

Sinomenine Provides Neuroprotection in Model of Traumatic Brain Injury via the Nrf2–ARE Pathway

“…The model of TBI used in the present study was based on Marmarou's weight-drop model with some modifications as previously described by Flierl et al (Flierl et al, 2009; Zhang et al, 2016). Mice were anesthetized in a closed container on a wire mesh over ether-soaked cotton and then placed onto the platform directly under the weight of the weight-drop device.…”