Secondary brain injury after parenchymal cerebral hemorrhage in humans: the role of oxidative stress and Endothelin-1

Abstract Background and aims Perihematomal hypoperfusion may lead to ischemic damage during intraparenchymal cerebral hemorrhage (ICH), resulting in worse prognosis. We aimed to (1) investigate the relationship between serum biomarkers related to oxidative stress and vasoactive substances and the occurrence of hypoperfusion and ischemic perihematomal lesions in ICH, (2) to evaluate their correlation with the volumetric evolution of the hematoma and perihematomal edema. Methods We enrolled 28 patients affected by ICH. Blood samples were collected at timepoint T0 (admission to Emergency-Room), T1 (12-24hs from symptoms onset), T2 (48- 72hs from onset), to measure Endothelin-1 (ET-1), nitrites/nitrates (NO), NADPH oxidase-2 (NOX-2), metalloproteinase-12 (MMP12) and asymmetric dimethylarginine (ADMA). Patients underwent brain MRI with perfusion study at T1 and MRI without perfusion at T2. Results 12 patients had ischemic perihematomal lesions at T1. A higher NOX-2 concentration at T0 was observed in patients with ischemic perihematomal lesions compared to those without, (34.9 pg/ml vs 22.4 pg/ml, p=0.051) and with a more severe perihematomal edema at T2 (37.99 pg/ml vs. 19.17 pg/ml, p=0.011). The ischemic perihematomal lesions development was also associated with an increased hematoma volume (p<0.005), perilesional edema (p=0.046), greater midline shift (p=0.036). ET-1 values at T1 inversely correlated with hemorrhage volume at T2 (ρ=-0.717, p=0.030). Conclusions NOX-2 seems to have a role in the development of ischemic perihematomal lesions. The association between higher ET-1 values and a lower hemorrhage volume could be related to the ET-1 vasoconstriction action on the ruptured vessel wall.