Phytochemical Sulforaphane Provides Cerebrovascular Protection in a Large Animal Model of Brain Oxidative Stress Injury Caused by Prolonged Neonatal Asphyxia
Authors: Liu Jianxiong , Hoover Daniel T , Fedinec Alexander L , Chandaka Giri K , Harsono Mimily , Pourcyrous Massroor , Leffler Charles W , Parfenova Helena 
Published: June 2021

Prolonged asphyxia in newborn infants may lead to cerebrovascular dysfunction and neurological complications. The neonatal brain is compromised by asphyxia/reventilation via a mechanism that involves oxidative stress. Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, such as brussels sprouts and broccoli, has antioxidant and cytoprotective properties. We tested the hypothesis that SFN exhibits protective properties in neonatal cerebral circulation during prolonged asphyxia. Newborn pigs provide a relevant model of neonatal cerebrovascular regulation. In the first series of experiments, we investigated whether SFN exhibited vasoactive properties in neonatal cerebral circulation by detecting responses of pial arterioles to topical and systemic administration of a synthetic D, L‐SFN. Intravital microscopy using the cranial window technique was implemented to detect these responses. Topical application of SFN (1 μM – 1 mM) to the cerebral surface produced dilation of pial arterioles up to 40% above the baseline. Systemic administration of SFN (0.4 mg/kg i.p.) also produced long lasting cerebral vasodilation 20–30% above the baseline, suggesting that SFN is a brainpermeable drug. In the second series of the experiments, we tested the effects of SFN on the cerebral vascular outcome of asphyxia. We used a model of prolonged asphyxia (50 minutes) that combined severe hypoxia (PaO2, 20–30 mm Hg), hypercapnia (PaCO2, 70–80 mm Hg), and acidosis (pH, 6.9–7.0) while avoiding cerebral ischemia. Cerebral vascular functions were tested in saline‐ and SFN‐treated newborn pigs 48 hours after asphyxia. Prolonged asphyxia followed by reventilation with room air caused injury to endothelial and astrocyte components of the neurovascular unit leading to cerebral vascular dysfunction. SFN (0.4 mg/kg, i.p.) administered 30 minutes before asphyxia prevented loss of cerebral vascular responses to endothelium‐ and astrocyte‐dependent stimuli. SFN administered 20 minutes after the onset of asphyxia also preserved cerebral vascular dilator functions. We then tested the anti‐apoptotic effects of SFN in the in vitro model of oxidative stress injury in primary cultures of cerebral endothelial cells and cortical astrocytes from newborn pigs. SFN (1–5 μM) effectively prevented apoptotic death of endothelial cells and astrocytes caused by oxidative stress induced by xanthine/xanthine oxidase, glutamate, and TNF‐alpha. Overall, SFN exhibited vasodilator and cerebroprotective properties in neonatal cerebral circulation and protected the neurovascular unit from oxidative stress injury caused by prolonged asphyxia/reventilation. We propose that SFN can be used as a novel therapeutic agent for preventing of hypoxic‐ischemic encephalopathy caused by prolonged neonatal asphyxia.Support or Funding InformationThe study was supported by National Institutes of Health: RO1HL42851 (CWL), RO1NS101717 (HP), and R01NS105655 (HP).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.