1 Center for System Biology and Institute for Innovation in Imaging, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
2 Neuroscience Center, Harvard Medical School, Massachusetts General Hospital, Boston, MA, USA.
J Cereb Blood Flow Metab. 2019 Sep;39(9):1864-1877. doi: 10.1177/0271678X18771978. Epub 2018 Apr 20.
Myeloperoxidase (MPO) is a pro-inflammatory enzyme abundantly secreted by activated myeloid cells after stroke. We show that when MPO activity is either blocked by the specific inhibitor 4-aminobenzoic acid hydrazide (ABAH) in wildtype (WT) mice or congenitally absent (MPO), there was decreased cell loss, including degenerating neurons and oligodendrocytes, in the ischemic brains compared to vehicle-treated WT mice after stroke. MPO inhibition also reduced the number of activated myeloid cells after ischemia. MPO inhibition increased cytoprotective heat shock protein 70 (Hsp70) by 70% and p-Akt by 60%, while decreased the apoptotic marker p53 level by 62%, compared to vehicle-treated mice after ischemia. Similarly, MPO inhibition increased the number of Hsp70/NeuN cells after stroke by 60%. Notably, MPO inhibition significantly improved neurological outcome compared with the vehicle-treated group after stroke. We further found longer treatment periods resulted in larger reduction of infarct size and greater neurobehavioral improvement from MPO inhibition, even when given days after stroke. Therefore, MPO inhibition with ABAH or MPO deficiency creates a protective environment that decreased inflammatory cell recruitment and increased expression of survival factors to improve functional outcome. MPO inhibition may represent a promising therapeutic target for stroke therapy, possibly even days after stroke has occurred.
髓过氧化物酶 (MPO) 是一种促炎酶，在中风后大量分泌于激活的髓样细胞中。我们发现，当 MPO 活性被野生型 (WT) 小鼠中的特异性抑制剂 4-氨基苯甲酰胺酸腙 (ABAH) 阻断或先天缺失 (MPO) 时，与中风后接受 vehicle 治疗的 WT 小鼠相比，缺血性大脑中的细胞丢失减少，包括变性神经元和少突胶质细胞。MPO 抑制也减少了缺血后激活的髓样细胞数量。MPO 抑制使细胞保护热休克蛋白 70 (Hsp70) 增加 70%，p-Akt 增加 60%，而使凋亡标志物 p53 水平降低 62%，与缺血后接受 vehicle 治疗的小鼠相比。同样，MPO 抑制使中风后 Hsp70/NeuN 细胞的数量增加了 60%。值得注意的是，与接受 vehicle 治疗的中风组相比，MPO 抑制显著改善了中风后的神经功能结局。我们进一步发现，较长的治疗时间会导致梗死面积更大的减少，以及 MPO 抑制后神经行为学的更大改善，即使在中风后几天给予治疗也是如此。因此，用 ABAH 或 MPO 缺乏抑制 MPO 会产生一种保护环境，减少炎症细胞募集并增加存活因子的表达，从而改善功能结局。MPO 抑制可能是中风治疗的一个有前途的治疗靶点，甚至在中风发生数天后也是如此。
