Corticosteroids have been used in the treatment of human traumatic brain injury (TBI), which is a leading cause of death and disability, but their efficiency is still a matter of debate. Dexamethasone was considered to delay post-traumatic inflammation and retard neuronal degeneration, resulting in attenuation of secondary injury following experimental TBI. In a rat TBI model, we have investigated the effects of dexamethasone on expression patterns of markers of inflammatory activation of microglia/macrophages by immunohistochemistry. Endothelial-monocyte activating polypeptide II (EMAP-II), P2X4 receptor (P2X4R) and allograft-inflammatory factor-1 (AIF-1) were reported to be associated with the activation of microglia/macrophages post central nervous system (CNS) injury and may play roles in inflammatory cascades of secondary brain damage. Dexamethasone significantly suppressed the accumulation of EMAP-II(+), P2X4R(+) or AIF(+) cells at Day-1 and 2 post-brain-trauma but not on Days 4 and 6, which is in accordance with the reported short- but not long-term protective effects of dexamethasone in TBI. These findings indicate a rather rapid but transient anti-inflammatory effect of dexamethasone in TBI.

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FTY720 (Fingolimod) is a novel type of immunosuppressive agent inhibiting lymphocyte egress from secondary lymphoid tissues thereby causing peripheral lymphopenia. FTY720 can inhibit macrophage infiltration into inflammatory lesions under pathological conditions. FTY720 has been clinically evaluated for prophylaxis of allograft rejection and treatment of multiple sclerosis, showing promising immunosuppressive effects. A robust inflammatory response after traumatic brain injury (TBI) plays an important role in the secondary or delayed injuries of TBI. Here we have investigated by immunohistochemistry in a rat TBI model the effects of FTY720 on early cell accumulation into the inflammatory tissue response and on expression of major histo-compatibility complex class II (MHC-II) and endothelial-monocyte activating polypeptide II (EMAP-II). Accumulation of MHC-II+ or EMAP-II+ cells became significant 1 day after injury and continuously increased during the early time periods. Further, double-staining experiments confirmed that the major cellular sources of MHC-II were reactive macrophages, however MHC-II+ cells only constituted a small subpopulation of reactive macrophages. Immediately after TBI, peripheral administration of FTY720 (1 mg/kg in 1 mL saline, every second day) significantly attenuated the accumulation of MHC-II+ macrophages from Day 1 to 4 and significantly attenuated the accumulation of EMAP-II+ macrophages/microglia at Day 4. Our findings show that FTY720 attenuates early accumulation of EMAP-II+ and MHC-II+ reactive monocytes following TBI, indicating that FTY720 might be a drug candidate to inhibit brain inflammatory reaction following TBI.

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