Inhibition of TREM-1 attenuates early brain injury after subarachnoid hemorrhage via downregulation of p38MAPK/MMP-9 and preservation of ZO-1

Abstract

Early brain injury (EBI) mainly leads to the poor outcome of subarachnoid hemorrhage (SAH), with which inflammation is closely associated. It was reported that triggering receptor expressed on myeloid cells-1 (TREM-1), a critical inflammatory amplifier, increased in cerebrospinal fluid of SAH patients in our recent research. This study was conducted to examine the effects of TREM-1 inhibition on EBI after experimental SAH (eSAH). The endovascular perforation model of SAH was produced and 120 rats were randomly divided into four groups as sham, SAH + vehicle and SAH + LP17 (1.0 mg/kg and 3.5 mg/kg). The LP17, a selective inhibitor of TREM-1, or vehicle was administered by an intraperitoneal injection 1 h post-modeling. Western blot analysis for TREM-1, p38 mitogen-activated protein kinase (p38MAPK), matrix metalloproteinase-9 (MMP-9) and zonula occludens-1 (ZO-1) was conducted at 24 h post-modeling. EBI was assessed in terms of mortality, neuroscore, brain edema, blood–brain barrier (BBB) disruption in 24 and 72 h. The results showed that TREM-1 was induced in brain after eSAH. Both high dose (3.5 mg/kg) and low dose (1.0 mg/kg) of Lp17 significantly inhibited the induction of TREM-1, but only high dose of LP17 improved neuroscore, brain edema, and BBB disruption which are associated with downregulation of p38MAPK/MMP-9 and subsequent preservation of ZO-1. Overall, the current study provides new evidence that TREM-1 may participate in the pathogenesis of SAH-induced EBI via promoting p38MAPK/MMP-9 activation and ZO-1 degradation, while TREM-1 inhibition attenuated the EBI severity obviously, providing a novel approach for the treatment of EBI.