Fingolimod Reduces The Inflammatory Response But Aggravates The Brain Injury In The Diffuse Brain Injury Model

Inflammatory response is an important cause to the secondary injury in traumatic brain injury(TBI),which is the key factor related to the recovery and prognosis for TBI patients.Diffuse brain injury is likely much worse than other types of brain injury,due to the extensive intracranial lesions,the more severe inflammation and immune responses.It has been reported that it can improve the therapeutic efficacy to inhibite early the inflammatory response after brain injury.F ingolimod,a novel immunosuppressive agent,has shown to improve the therapeutic efficacy and prognosis of patients suffering from multiple sclerosis and stroke(hemorrhagic and ischemic stroke).Previous studies of our team have also confirmed that fingolimod can improve the prognosis of the TBI rat models of moderate injury degree resulted from the control cortical injury(CCI)facility.Thus,we hypothesize that fingolimod reduce the inflammatory response in the diffuse brain injury(DBI),which is induced by the Marmaro model,and improve its prognosis.Objective: To observe the therapeutic effect of fingolimod on DBI rat models in the inflammatory response,in order to provide the new data for proposing the new diagnosis and treatment strategy for brain injury.Contents: In this study,we investigated the e ffects of fingolimod on the immune cells in peripheral blood and the local injuried brain tissue of the DBI rats.The quantity of inflammatory cells and the damage of nerve cells were measured.The changes of cytokines in the injuried brain tissue of the DBI rats were measured.The changes of neurological behavor and functions were observed.Methods: 250 g male S-D rats were used as the experimental animals and the DBI was induced based on the Marmaro model.The rats were divided into three groups: the experimental DBI rats,the control DBI rats and the sham groups without the brain injury.The rats in the experimental group were treated with intraperitoneal injection of fingolimod at the dose of 0.5mg / kg within 30 minutes after injury and continued the similar therapy with two 24 h intervals for 3 days.With the same volume,application frequency and the injection way to fingolimod,the rats in the control group and the sham one were treated with the saline.Medicine was taken once every 24 hours for 3 days.The Treg cells and T cells in the peripheral blood were both quantified and analyzed with the flow cytometry.The changes of the inflammatory cytokines in the injuried brain tissue were detected with cytokine arrays.The brain edema was analyzed with the dry-wet method.The expression of C laudin 5 and ZO-1 in the injuried brain tissue was inspected with the Western Blotting.The neurological behavor of the rats was evaluated with the modified mNss score.The neurological function was tested on the rods at 1,3,7 and 14 days after injury.Result: In addition of the significant neurological symptoms and signs,the expression of ?-APP in the brain tissue of the DBI models was also significantly higher than the sham models and it indicates that the DBI model was established successfully.Compared with the control group,the number of apoptotic cells,the expression of ?-APP,C laudin 5 and ZO-1 and the inflammatory cytokines such as IL-10 in the injured brain tissue of the experimental group were significantly increased(p <0.01 or p<0.05).In addition,the quantity of the Treg cells in the peripheral blood in the experimental group was also increased(p= 0.03)when compared with the control group,while CD4 + and CD8 + T lymphocytes decreased,but the proportion of CD8 + T lymphocytes increased(p = 0.03).The activated microglia was decreased in the injured brain tissue by fingolimod when compared with the control group(p<0.01).Futher more,the scores of mNSS at the 14 days after injury were significantly higher than the control group(p <0.05),and the prognosis was worse in DBI rats of the experimental group than the ones in the control group(p<0.05).Conclusion: There is severe immunosuppression in DBI rats.Fingolimod is able to reduce the number of activated microglia,downregulate the inflammatory response in the injured brain tissue of the DBI rats,repair the damaged blood-brain barrier,reduce brain tissue edema.However,fingolimod leads to more apoptosis in the neural tissue,contributing to a worse prognosis of the DBI rats.