The Role of Oxidative Stress in Microvascular Disturbances after Experimental Subarachnoid Hemorrhage
Oxidative stress was shown to play a crucial role in the diverse pathogenesis of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Microcirculatory dysfunction is thought to be an important and fundamental pathological change in EBI. However, other than blood-brain barrier (BBB) disruption, the influence of oxidative stress on microvessels remains to be elucidated. The aim of this study was to investigate the role of oxidative stress on microcirculatory integrity in EBI. SAH was induced in male Sprague-Dawley rats using an endovascular perforation technique. A free radical scavenger, edaravone, was administered prophylactically by intraperitoneal injection. SAH grade, neurological score, brain water content, and BBB permeability were measured at 24 h after SAH induction. In addition, cortical samples taken at 24 h after SAH were analyzed to explore oxidative stress, microvascular mural cell apoptosis, microspasm, and microthrombosis. Edaravone treatment significantly ameliorated neurological deficits, brain edema, and BBB disruption. In addition, oxidative stress-induced modifications and subsequent apoptosis of microvascular endothelial cells and pericytes increased after SAH induction, while the administration of edaravone suppressed this. Consistent with apoptotic cell inhibition, microthromboses were also inhibited by edaravone administration. Oxidative stress plays a pivotal role in the induction of multiple pathological changes in microvessels in EBI. Antioxidants are potential candidates for the treatment of microvascular disturbances after SAH.
KeywordsEarly brain injury Subarachnoid hemorrhage Oxidative stress Microvessel
The authors thank Mark Inglin (University of Basel) for his editorial assistance.
This study was supported partially by JSPS KAKENHI Grant Number JP16K19993 (to MN).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that no conflict of interest exists.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
- 3.Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S, et al. Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (conscious-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke. 2008;39(11):3015–21.PubMedGoogle Scholar
- 4.Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A, et al. Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (conscious-2). Lancet Neurol. 2011;10(7):618–25.PubMedGoogle Scholar
- 8.Neulen A, Meyer S, Kramer A, Pantel T, Kosterhon M, Kunzelmann S, et al. Large vessel vasospasm is not associated with cerebral cortical hypoperfusion in a murine model of subarachnoid hemorrhage. Transl Stroke Res. 2018. https://doi.org/10.1007/s12975-018-0647-6.
- 13.Endo H, Nito C, Kamada H, Yu F, Chan PH. Reduction in oxidative stress by superoxide dismutase overexpression attenuates acute brain injury after subarachnoid hemorrhage via activation of Akt/glycogen synthase kinase-3beta survival signaling. J Cereb Blood Flow Metab. 2007;27(5):975–82.PubMedGoogle Scholar
- 16.Shi X, Fu Y, Zhang S, Ding H, Chen J. Baicalin attenuates subarachnoid hemorrhagic brain injury by modulating blood-brain barrier disruption, inflammation, and oxidative damage in mice. Oxidative Med Cell Longev. 2017;2017:1401790.Google Scholar
- 26.Yabluchanskiy A, Ma Y, Iyer RP, Hall ME, Lindsey ML. Matrix metalloproteinase-9: many shades of function in cardiovascular disease. Physiology (Bethesda). 2013;28(6):391–403.Google Scholar
- 28.Duris K, Lipkova J, Splichal Z, Madaraszova T, Jurajda M. Early inflammatory response in the brain and anesthesia recovery time evaluation after experimental subarachnoid hemorrhage. Transl Stroke Res. 2018. https://doi.org/10.1007/s12975-018-0641-z.
- 29.Blecharz-Lang KG, Wagner J, Fries A, Nieminen-Kelhä M, Rösner J, Schneider UC, et al. Interleukin 6-mediated endothelial barrier disturbances can be attenuated by blockade of the IL6 receptor expressed in brain microvascular endothelial cells. Transl Stroke Res. 2018;9:631–42. https://doi.org/10.1007/s12975-018-0614-2.
- 55.Suzuki S, Kimura M, Souma M, Ohkima H, Shimizu T, Iwabuchi T. Cerebral microthrombosis in symptomatic cerebral vasospasm—a quantitative histological study in autopsy cases. Neurol Med Chir (Tokyo). 1990;30(5):309–16.Google Scholar