Are Blood-brain Interfaces Efficient in Protecting the Brain from Reactive Molecules ?

Ghersi-Egea, Jean-François; Strazielle, Nathalie; Murat, Audrey; Edwards, Jonathan; Belin, Marie‐Françoise

doi:10.1007/978-1-4615-0667-6_59

Cited by 8 publications

(5 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Brain CYP metabolic enzymes were previously suggested to interfere with drug brain biodistribution (Ghersi-Egea et al, 1995, Ghersi-Egea et al, 2001, Dauchy et al, 2008, Dauchy et al, 2009, Ghosh et al, 2011b), to be involved in detoxification processes, or in the production of neurotoxins (Ghosh et al, 2012). Brain CYP could also play a role in brain drug resistance (Ghosh et al, 2011b).…”

Section: Discussionmentioning

confidence: 99%

“…CYP exert their primary functions in the liver (Brodie et al, 2013). In addition to hepatic drug metabolism and detoxification, a local brain drug biotransformation may also influence the pharmacokinetic and pharmacodynamic fate of CNS drugs (Ghersi-Egea et al, 1993, Ghersi-Egea et al, 2001, Bauer et al, 2006, Dauchy et al, 2008, Ghosh et al, 2010, Ghosh et al, 2011b). …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression

et al. 2014

View full text Add to dashboard Cite

P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. Status epilepticus (SE) was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18–24 hours after SE by immunohistochemistry. Co-localization with NEUN, GFAP and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro. CYP2E1 expression was investigated in brain resections from a cohort of drug resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro, ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression

et al. 2014

View full text Add to dashboard Cite

show abstract

“…The expression of metabolic enzymes in the rodent and human brain has been known for many years (Ghersi‐Egea et al., , , ). However, only recently was this evidence corroborated by studies conducted using an immortalized brain capillary endothelial cell line and isolated human brain microvessels (Dauchy et al., , ; Shawahna et al., ).…”

Section: Discussionmentioning

confidence: 99%

Expression and functional relevance of UGT1A4 in a cohort of human drug‐resistant epileptic brains

et al. 2013

View full text Add to dashboard Cite

Summary Purpose Brain drug bioavailability is regulated by the blood–brain barrier (BBB). It was recently suggested that cytochrome P450 (CYP) enzymes could act in concert with multidrug transporter proteins to regulate drug penetration and distribution into the diseased brain. The possibility that phase II metabolic enzymes could be expressed in the epileptic brain has been not evaluated. Phase II enzymes are involved in the metabolism of common antiepileptic drugs (AEDs). Methods Phase II enzyme UGT1A4 brain expression was evaluated in temporal lobe resections from patients with epilepsy. UGT1A4 expression was determined by western blot and immunocytochemistry in primary cultures of human drug-resistant brain endothelial human brain epileptic endothelial cells (EPI-EC)s and commercially available control cells human brain microvascular endothelial cells (HBMECs). Lack of DNA condensation measured by 4′,6-diamidino-2-phenylindole (DAPI) was used as a surrogate marker of cell viability and was correlated to UGT1A4 expression high performance liquid chromatography ultraviolet detection (HPLC-UV) was used to quantify lamotrigine metabolism by EPI-EC and HBMEC. The appearance of the specific lamotrigine metabolite, 2-n glucuronide (MET-1), was also evaluated. Lamotrigine and MET-1 levels were measured in selected surgical brain and matched blood samples. Key Findings UGT1A4 expression was observed in BBB endothelial cells and neurons. Our quantification study revealed variable levels of UGT1A4 expression across the brain specimens analyzed. Neurons devoid of UGT1A4 expression displayed nuclear DAPI condensation, a sign of cellular distress. UGT1A4 overexpression in EPI-EC, as compared to HBMEC, was reflected by a proportional increase in lamotrigine metabolism. The lamotrigine metabolite, MET-1, was formed in vitro by EPI-EC and, to a lesser extent, by HBMEC. HPLC-UV measurements of brain and blood samples obtained from patients receiving lamotrigine prior to surgery revealed the presence of lamotrigine and its metabolites in the brain. Significance These initial results suggest the presence of a phase II enzyme in the epileptic brain. Further studies are required to fully describe the pattern of brain UGT1A4 expression in relation to clinical variables and drug resistance.

show abstract

“…The choroid plexuses are a first line defence for the brain, protecting it against acute neurotoxic insults through a complex, multilayered detoxification system (Gao and Meier, 2001;Ghersi-Egea et al, 2001). The choroid plexuses aid or impede the overall bio-distribution of drugs and toxic compounds by being the source of a full compliment of a number of metabolic enzymes.…”

Section: Alterations Of Csf Manufacture and Homeostasismentioning

confidence: 99%

Cerebrospinal Fluid Proteomes: From Neural Development to Neurodegenerative Diseases

Parada¹,

Parvas²,

Bueno

2007

View full text Add to dashboard Cite

Global characterisation of proteins and the comparison between proteomes is providing new insights into general biological structures and processes, as well as between physiological and pathological conditions. During both embryonic development and adult life, brain cavities and ventricles are filled with a complex protein-rich fluid, the cerebrospinal fluid (CSF). In the last few years, it has been suggested that adult CSF has a key function as a fluid pathway for delivering diffusible signals to the brain, thus affecting the behaviour of specific brain parenchyma cells, particularly the putative neural stem cells. Accordingly, some pathologies that affect the central nervous system (CNS), such as neurodegenerative diseases and/or neurological disorders, are reflected in CSF protein content, either as a cause or as a consequence. Adult CSF is considered to be the successor of embryonic CSF (E-CSF). Most of the proteins contained within E-CSF, as analysed in avians (chick) and mammals (rat and human), are also detected in adult humans, suggesting that some of their roles in CNS cell behaviour are similar. Despite the heterogeneity of the currently available data, which is due to technical differences in the proteomic analyses, the use of different model systems and the great variety of sample sources, it is increasingly clear that this fluid regulates the behaviour of neural stem cells throughout development and during adult life, thus suggesting a possible approach to brain cell therapies. This review focuses on current data regarding CSF proteomes in relation to CSF functions in both physiological and pathological conditions, as well as on CSF manufacture.

show abstract

Are Blood-brain Interfaces Efficient in Protecting the Brain from Reactive Molecules ?

Cited by 8 publications

References 10 publications

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression

Expression and functional relevance of UGT1A4 in a cohort of human drug‐resistant epileptic brains

Cerebrospinal Fluid Proteomes: From Neural Development to Neurodegenerative Diseases

Contact Info

Product

Resources

About