Sulfuraphane (SFN) activation of nuclear factor E2‐related factor 2 (Nrf2) increases expression and transport activity of P‐glycoprotein (P‐gp) and breast cancer related protein (Bcrp) at the blood‐brain barrier (BBB)

Abstract

Nrf2 is a redox‐sensitive transcription factor that plays a critical role in cellular defenses against oxidative/electrophilic stress. Administering SFN, a Nrf2 ligand present in cruciferous vegetables, is neuroprotective in cerebral ischemia, traumatic brain injury and subarachnoid hemorrhage; Nrf2 is proposed as a therapeutic target. Here we assess the effects of Nrf2 activation on the transport activity and expression of the BBB drug efflux pumps, P‐gp and Bcrp using isolated rat and mouse brain capillaries. Capillaries from rats dosed with SFN (10 mg/kg i.p.) exhibited 2–3‐fold increased P‐gp transport activity and P‐gp and Bcrp protein expression. Exposing isolated brain capillaries to 0.1–1 uM SFN for 3 h increased P‐gp and Bcrp activity and expression. Inhibiting transcription or translation abolished upregulation of transport. In brain capillaries from Nrf2‐null mice, SFN did not alter transport activity. Surprisingly, Nrf2 signaled indirectly through p53 and NF‐kB to increase transporter activity/expression. Thus, a consequence of Nrf2‐induced neuroprotection is selective tightening of the BBB to therapeutic drugs. Supported by the Intramural Research Program NIH/NIEHS.