Abstract
Sulforaphane (SFN) has been shown to protect the brain vascular system and effectively reduce ischemic injuries and cognitive deficits. Given the robust cerebrovascular protection afforded by SFN, the objective of this study was to profile these effects in vitro using primary mouse brain microvascular endothelial cells and focusing on cellular redox, metabolism and detoxification functions. We used a mouse MitoChip array developed and validated at the FDA National Center for Toxicological Research (NCTR) to profile a host of genes encoded by nuclear and mt-DNA following SFN treatment (0–5 µM). Corresponding protein expression levels were assessed (ad hoc) by qRT-PCR, immunoblots and immunocytochemistry (ICC). Gene ontology clustering revealed that SFN treatment (24 h) significantly up-regulated ~50 key genes (>1.5 fold, adjusted p < 0.0001) and repressed 20 genes (<0.7 fold, adjusted p < 0.0001) belonging to oxidative stress, phase 1 & 2 drug metabolism enzymes (glutathione system), iron transporters, glycolysis, oxidative phosphorylation (OXPHOS), amino acid metabolism, lipid metabolism and mitochondrial biogenesis. Our results show that SFN stimulated the production of ATP by promoting the expression and activity of glucose transporter-1, and glycolysis. In addition, SFN upregulated anti-oxidative stress responses, redox signaling and phase 2 drug metabolism/detoxification functions, thus elucidating further the previously observed neurovascular protective effects of this compound.
Highlights
Sulforaphane (SFN) has been shown to protect the brain vascular system and effectively reduce ischemic injuries and cognitive deficits
By western blotting, real-time quantitative reverse transcription polymerase chain reaction and integrated cell culture (ICC), we investigated the cellular impact of SFN treatment using mouse primary brain microvascular endothelial cells
We show that SFN promotes Glut[1] expression and activity (Fig. 2) in brain vascular endothelium. 24 h exposure to SFN (5 μM) promoted the expression of the glucose transporter Glut[1] as demonstrated by western blots (WB) analyses and immunofluorescence in mouse blood-brain barrier (BBB) endothelial cells (Fig. 2A)
Summary
Sulforaphane (SFN) has been shown to protect the brain vascular system and effectively reduce ischemic injuries and cognitive deficits. Strong causative link between oxidative and pro-inflammatory stresses, brain microvascular dysfunction, and CNS disease[7] Overarching evidence indicates that sustained oxidative stress generated by pro-oxidant and pro-inflammatory stimuli, can negatively impact BBB physiology and function[3,8,9,10,11] In this respect, sulforaphane, a naturally occurring organosulfur compound generated from cruciferous vegetables (e.g., broccoli), is a potent inducer of antioxidant[12] and phase-2 detoxifying enzymes[13]. Dysfunction in these organelles could potentially lead to various degenerative diseases and disorders in these organs as well as various drug-induced toxicities, as several therapeutic drugs are known to target mitochondria[31,32] Based on these well-established evidences, we sought to profile the impact of SFN on nuclear and mitochondrial DNA gene expression and to investigate SFN modulation of cellular redox and metabolism interplay at the brain vascular endothelium
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