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

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.

Choroid plexus glutathione peroxidases are instrumental in protecting the brain fluid environment from hydroperoxides during postnatal development.

Hydrogen peroxide, released at low physiological concentration, is involved in different cell signaling pathways during brain development. When released at supraphysiological concentrations in brain fluids following an inflammatory, hypoxic, or toxic stress, it can initiate lipid peroxidation, protein, and nucleic acid damage and contribute to long-term neurological impairment associated with perinatal diseases. We found high glutathione peroxidase and glutathione reductase enzymatic activities in both lateral and fourth ventricle choroid plexus tissue isolated from developing rats, in comparison to the cerebral cortex and liver.

Barriers to Drug Distribution into the Perinatal and Postnatal Brain.

Drug bioavailability to the developing brain is a major concern in the treatment of neonates and infants as well as pregnant and breast-feeding women. Central adverse drug reactions can have dramatic consequences for brain development, leading to major neurological impairment. Factors setting the cerebral bioavailability of drugs include protein-unbound drug concentration in plasma, local cerebral blood flow, permeability across blood-brain interfaces, binding to neural cells, volume of cerebral fluid compartments, and cerebrospinal fluid secretion rate.

Glutathione Conjugation at the Blood-CSF Barrier Efficiently Prevents Exposure of the Developing Brain Fluid Environment to Blood-Borne Reactive Electrophilic Substances.

Exposure of the developing brain to toxins, drugs, or deleterious endogenous compounds during the perinatal period can trigger alterations in cell division, migration, differentiation, and synaptogenesis, leading to lifelong neurological impairment. The brain is protected by cellular barriers acting through multiple mechanisms, some of which are still poorly explored. We used a combination of enzymatic assays, live tissue fluorescence microscopy, and an cellular model of the blood-CSF barrier to investigate an enzymatic detoxification pathway in the developing male and female rat brain.