20-HETE Synthesis Inhibition Promotes Cerebral Protection after Intracerebral Hemorrhage without Inhibiting Angiogenesis
20-HETE, an arachidonic acid metabolite synthesized by cytochrome P450 4A, plays an important role in acute brain damage from ischemic stroke or subarachnoid hemorrhage. We tested the hypothesis that 20-HETE inhibition has a protective effect after intracerebral hemorrhage (ICH) and then investigated its effect on angiogenesis. We exposed hippocampal slice cultures to hemoglobin and induced ICH in mouse brains by intrastriatal collagenase injection to investigate the protective effect of 20-HETE synthesis inhibitor N-hydroxy-N'-(4-n-butyl-2-methylphenyl)-formamidine (HET0016). Hemoglobin-induced neuronal death was assessed by propidium iodide after 18 h in vitro. Lesion volume, neurologic deficits, cell death, reactive oxygen species (ROS), neuroinflammation, and angiogenesis were evaluated at different time points after ICH. In cultured mouse hippocampal slices, HET0016 attenuated hemoglobin-induced neuronal death and decreased levels of proinflammatory cytokines and ROS. In vivo, HET0016 reduced brain lesion volume and neurologic deficits, and decreased neuronal death, ROS production, gelatinolytic activity, and the inflammatory response at three days after ICH. However, HET0016 did not inhibit angiogenesis, as levels of CD31, VEGF, and VEGFR2 were unchanged on day 28. We conclude that 20-HETE is involved in ICH-induced brain damage. Inhibition of 20-HETE synthesis may provide a viable means to mitigate ICH injury without inhibition of angiogenesis.
Han, X., Zhao, X., Lan, X., Li, Q., Gao, Y., Liu, X., Wan, J., Yang, Z., Chen, X., Zang, W., Guo, A., Falck, J., Koehler, R., & Wang, J. (2019). 20-HETE Synthesis Inhibition Promotes Cerebral Protection after Intracerebral Hemorrhage without Inhibiting Angiogenesis. Journal of Cerebral Blood Flow and Metabolism, 39 (8), 1531-1543. https://doi.org/10.1177/0271678X18762645