Mechanism Of Myeloperoxidase In Secondary Brain Injury After Intracerebral Hemorrhage

Background and purpose: Intraerebral hemorrhage is a disease with high mortality and disability,bringing great burden to the society and the family.And there is no unified and standardized treatment for it so far.The mechanism of secondary brain injury caused by intracerebral hemorrhage is not completely clear,but it includes inflammation,destruction of blood-brain barrier,brain edema,cytotoxicity,oxidative stress and so on.Myeloperoxidase(MPO)can cause neuronal degeneration,necrosis and brain edema by regulating the balance of immunity and inflammation,destroy the blood-brain barrier and participate oxidative stress in many nervous system diseases.A recent clinical study has shown that the concentration of serum MPO in patients with intracerebral hemorrhage is significantly increased,which is significantly correlated with severity and prognosis of the patients.N-acetyl lysyltyrosylcysteine amide(KYC)is a new tripeptide inhibitor of MPO with high specificity,high efficiency and nontoxicity.Some studies have suggested that it may be an effective drug for the treatment of multiple sclerosis and a highly effective therapeutic agent for stroke patients.The purpose of this study is to explore the role and possible mechanism of MPO in secondary brain injury after intracerebral hemorrhage,and potential targets and therapeutic drugs.We hope to provide a new method and theoretical basis for the clinical treatment of patients with intracerebral hemorrhage,so as to improve the neurological impairment of patients with intracerebral hemorrhage.Methods: In this study,the mouse model of intracerebral hemorrhage was established by autologous blood injection.KYC was used as MPO inhibitor,the mice were divided into three groups: Sham group,ICH+KYC group and ICH+PBS group.The neurological damage of mice after intracerebral hemorrhage was evaluated by mNSS,and MPO activity assay,Western blot,ELISA,immunofluorescence staining and FJB staining were used to analyze the effects of inhibition of MPO activity on the expression of inflammatory mediators,activation of microglia and neuronal degeneration after intracerebral hemorrhage in mice.Results: After inhibition of MPO in acute phase of intracerebral hemorrhage,it was found that the mNSS score of mice in ICH+KYC group decreased faster than that in ICH+PBS group.On the 3rd day of intracerebral hemorrhage,the activity of MPO in serum and brain tissue around hematoma in ICH+PBS group was significantly higher than that in ICH+KYC group,and the activity in Sham group was the lowest.Compared with ICH+PBS group,the expression of IL-1 ?,IL-6,HMGB-1,MMP-9,TLR4,NF-? B and the number of activated microglia in ICH+KYC group were lower while the expression of IL-10 was higher,and the expression of IL-1 ?,IL-6,HMGB-1 and MMP-9 was the lowest in Sham group.The number of degenerative neurons in ICH+PBS group was significantly higher than that in ICH+KYC group.Conclusions: The activity of MPO in serum and brain tissue around hematoma increased significantly in the acute phase of intracerebral hemorrhage,and KYC could significantly inhibit the activity and expression of MPO.Inhibition of MPO in acute phase of intracerebral hemorrhage can reduce the inflammatory reaction of brain tissue around hematoma,reduce neuronal damage,indirectly reduce the damage of bloodbrain barrier and improve neurological function,and KYC may be a potential effective drug for the treatment of intracerebral hemorrhage which needs further study.