The glutathione-dependent neuroprotective activity of the blood-CSF barrier is inducible through the Nrf2 signaling pathway during postnatal development.

Abstract

Background: Choroid plexuses regulate the exchanges between the blood and the CSF, and provide trophic factors necessary to brain development. They also express detoxifying enzymes that protect the developing brain from harmful substances. Targeting the Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) signaling pathway may enhance the detoxification capabilities of choroid plexuses that are linked to glutathione conjugation, but little is known about mechanisms of enzyme induction in this tissue.

Methods: Rat pups were treated with dimethylfumarate and the subcellular localization of Nrf2 was analyzed in the choroidal tissue by confocal imaging. Glutathione-S-transferase (GST) activity was assessed ex vivo in the choroidal tissue, and 1-chloro-2,4-dinitrobenzene, a toxicant and prototypic GST substrate, was used to evaluate in vivo the efficiency of the glutathione-dependent enzymatic barrier function of choroid plexuses. Nrf2 knockout rat pups were used to establish the Nrf2 dependency of GST induction in this tissue.

Results: We show an early postnatal expression of Nrf2 in the rat choroidal tissue. Treatment of rat pups with dimethylfumarate triggers Nrf2 nuclear translocation in choroidal epithelial cells. This treatment increases GST activity in choroid plexus, and reduces the blood-to-CSF permeation of 1-chloro-2,4-dinitrobenzene. In Nrf2 knockout rats, the constitutive activity of the choroidal glutathione-dependent detoxifying machinery is maintained, but the efficacy of dimethylfumarate to induce glutathione conjugation in the choroid plexuses is strongly reduced, indicating that dimethylfumarate acts mainly through the Nrf2 signaling pathway.

Conclusions: This work shows that the glutathione-dependent detoxifying function of the blood-CSF barrier can be pharmacologically enhanced through the Nrf2 signaling pathway to better protect the neural fluid environment from drug and toxic accumulation during the neonatal period.