O-dodecyl P-methylenebisphosphonic Calix[4]arene Micelles Containing Dauricine Can By Remodeling The Brain Microenvironment To Treat Intracerebral Hemorrhage And Mechanism Research

Objective:It is proved that O-dodecyl p-methylenebisphosphonic calix[4]arene micelles containing dauricine?DPM?can better treat intracerebral hemorrhage by remodeling the microenvironment in the brain.Methods:DPM were fabricated by a improved thin-film hydration method,then calculated the physical characterizations such as encapsulation efficiency and drug loading,SH-SY5Y cells were induced by Fe²⁺that simulated neurons damage model in vitro.Respectively with dauricine?DRC?,O-dodecyl p-methylenebisphosphonic calix[4]arene micelles?PM?,O-dodecyl p-methylenebisphosphonic calix[4]arene micelles containing dauricine?DPM?,testing the cell survival rate/reactive oxygen species?ROS?and cell apoptosis of the each group.Then ICH was induced using the autologous whole blood double infusion model,mice were randomly divided into the following five groups,sham group,vehicle group,DRC group,PM group and DPM group.The brain tissues in mice were observed and analyzed through the evaluation of the behavior?the brain water content?the permeability of blood brain barrier of each group,and by using in vivo imaging,MRI,pathology,Western blot and immunofluorescence methods.Results:in this study,we found that compared with simple DRC and PM,DPM can effectively increase the activity of SH-SY5Y induced by Fe²⁺,meanwhile reduce the intracellular ROS content and the cell apoptosis rate.By in vivo studies also found that DPM can be accumulated in the brain of the mouse,and can effectively alleviate the neural function of mice,reduce the water content of brain,repair the damage of blood brain barrier and reduce inflammation in the brain.At the same time,we also found that DPM can regulate the GPX4 protein of the ferroptosis pathway and the key protein of apoptosis such as Bcl-2?Caspase-3?Bax.Conclusion:In this study provide the preliminary evidence that the DPM may be effective in reconstructing the intracerebral microenvironment for the treatment of intracerebral hemorrhage by inhibiting ferroptosis and apoptosis.