Progesterone-mediated Angiogenesis Inducing Neurorestorationintraumatic Brain Injury Rats Is Mediated ByProgesterone Receptor

There is no effective drug for the traumatic brain injury(TBI) even after world wide hard exploration for more than five decades. Progesterone is the first drug approved by NIH to be applied in the III phase clinical trial for TBI in more than 30 years research. Thus the research of progesterone on TBI becomes one of the hot issues in TBI field.And at the same time, the research about theprogesterone receptor were mainly focus on the hypothalamus and the reproductive function.But,how progesterone receptor function after TBI, There were only few researches.The main purpose of this research was to explore the neurorestoration of progesterone on TBI rats,and how progesterone affect the brain edema and angiogenesis after TBI and to detect the role of progesterone receptor in this process.Contents:There are often occur the severe brain edema and deterioration of neurological function after TBI.The main contents of this study were to detect the effect of progesterone on TBI rats neurofuntion recevery, the brain edema levels, angiogenesis and related DLL4/Notch1 signaling pathway.Further,we employed the progesterone receptor modulator to explore the effection of progesterone receptor on TBI.Methods:The subjects in this study were the male Wistar rat.We use the electronically controlled cortical impact device to produce the TBI rat model.The progesterone receptor modulator, ulipristal acetate(UPA),was uesd to explore the role of progesterone receptor(PR) in this process.The TBI rats were randomly divided into three groups,Control group:intraperitoneal injection with DMSO;PROG group: intraperitoneal injection with progesterone(16mg/kg)dissolved in DMSO;PROG +UPA group: intraperitoneal injection with progesterone(16mg/kg) and UPA(3mg/kg)dissolved in DMSO. There were 3 times to give the injection respectively at the 6 hours and 2, 3 day after TBI.The neurological functions of TBI rats were evaluated by a modified neurological severity score(mNSS). Using Western blotting to assay the expressions of the angiogenesis related proteins DLL4 and Notch1.Immunohistochemical assessmentwas employed to assay the positive rates of vWF and Occludin. Blood brain barrier(BBB) leakage measurements were also employed.Result: After administrating progesterone, a significant improvement of neurological function and the restoration of the leaked BBB were observed as well as an increased expression of vWF and Occludin in the TBI rats. The reduction in the brain water content were also detected. When UPA was administered with PROG, the neural restoration was attenuated and the increased molecular proteins expression of the angiogenesis signal pathway are all reversed. It could be concluded that the PROG inducing angiogenesis related neural restoration could be reversed by PR inhibitor.Conclusion:Progesterone could improve the neurological function recovery after traumatic brain injury,reduce the brain edema,promoting angiogenesis.In this process,progesterone may positive regulate the DLL4/Notch1 signaling pathway through progesterone receptor.