Oleanolic acid exerts neuroprotective effects in subarachnoid hemorrhage rats through SIRT1-mediated HMGB1 deacetylation

Abstract

Anti-inflammatory therapy for early brain injury after subarachnoid hemorrhage is a promising treatment for improving the prognosis. HMGB1 is the initiator of early inflammation after subarachnoid hemorrhage. Oleanolic acid is a natural pentacyclic triterpenoid compound with strong anti-inflammatory activity. It can relieve early brain injury in subarachnoid hemorrhage rats, but its mechanism is not very clear. Here, we study the potential mechanism of Oleanolic acid in the treatment of subarachnoid hemorrhage. First, we demonstrated that oleanolic acid alleviated early brain injury after subarachnoid hemorrhage, including improvement of grading score, neurological score, brain edema and permeability of brain blood barrier. Then we found that oleanolic acid could inhibit the transfer of HMGB1 from nucleus to cytoplasm and reduce the level of serum HMGB1. Furthermore, we found that oleanolic acid decreased the acetylation level of HMGB1 by increasing SIRT1 expression rather than by inhibiting JAK/STAT3 pathway. SIRT1 inhibitor sirtinol eliminated all beneficial effects of oleanolic acid on subarachnoid hemorrhage, which indicated that oleanolic acid inhibited the acetylation of HMGB1 by up regulating SIRT1. In addition, oleanolic acid treatment also reduced the levels of TLR4 and apoptosis related factors and reduced neuronal apoptosis after subarachnoid hemorrhage. In summary, our findings suggest that oleanolic acid may activate SIRT1 by acting as an activator of SIRT1, thereby reducing the acetylation of HMGB1, thus playing an anti-inflammatory role to alleviate early brain injury after subarachnoid hemorrhage.