PT  - JOURNAL ARTICLE
AU  - Kratzer Ingrid
AU  - Strazielle Nathalie
AU  - Saudrais Elodie
AU  - Mönkkönen Kati
AU  - Maleval Céline
AU  - Blondel Sandrine
AU  - Ghersi-Egea Jean-François
TI  - Glutathione conjugation at the blood-CSF barrier efficiently prevents exposure of the developing brain fluid environment to blood-borne reactive electrophilic substances
AID  - 10.1523/JNEUROSCI.2967-17.2018
DP  - 2018 Mar 05
TA  - The Journal of Neuroscience
PG  - 2967-17
4099  - http://www.jneurosci.org/content/early/2018/03/05/JNEUROSCI.2967-17.2018.short
4100  - http://www.jneurosci.org/content/early/2018/03/05/JNEUROSCI.2967-17.2018.full
AB  - 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 life-long 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 in vitro cellular model of the blood-CSF barrier to investigate an enzymatic detoxification pathway in the developing male and female rat brain. We show that during the early postnatal period the choroid plexus epithelium forming the blood-CSF barrier and the ependymal cell layer bordering the ventricles harbor a high detoxifying capacity that involves glutathione-S-transferases. Using a functional knockdown rat model for choroidal glutathione conjugation, we demonstrate that already in neonates, this metabolic pathway efficiently prevents the penetration of blood-borne reactive compounds into CSF. The versatility of the protective mechanism results from the multiplicity of the glutathione-S-transferase isoenzymes, which are differently expressed between the choroidal epithelium and the ependyma. The various isoenzymes display differential substrate specificities, which greatly widens the spectrum of molecules that can be inactivated by this pathway. In conclusion, the blood-CSF barrier and the ependyma are identified as key cellular structures in the CNS to protect the brain fluid environment from different chemical classes of potentially toxic compounds during the postnatal period. This metabolic neuroprotective function of brain interfaces ought to compensate for the liver postnatal immaturity.Significant statementBrain homeostasis requires a stable and controlled internal environment. Defective brain protection during the perinatal period can lead to life-long neurological impairment. We demonstrate that the choroid plexus forming the blood-CSF barrier is a key player in the protection of the developing brain. Glutathione-dependent enzymatic metabolism in the choroidal epithelium inactivates a broad spectrum of noxious compounds, efficiently preventing their penetration into the CSF. A second line of detoxification is located in the ependyma separating the CSF from brain tissue. Our study reveals a novel facet of the mechanisms by which the brain is protected at a period of high vulnerability, at a time when the astrocytic network is still immature and liver xenobiotic metabolism is limited.