Neurovascular Drug Biotransformation Machinery in Focal Human Epilepsies: Brain CYP3A4 Correlates with Seizure Frequency and Antiepileptic Drug Therapy

Williams, S.P.; Hossain, Mohammed Kamal; Ferguson, Lisa; Busch, Robyn M.; Marchi, Nicola; González-Martínez, Jorge; Perucca, Emilio; Najm, Imad; Ghosh, Chaitali

doi:10.1007/s12035-019-01673-y

Cited by 16 publications

(22 citation statements)

References 45 publications

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“…These results suggest that the local biotransformation of anti-seizure medication or dysfunctional drug transport mechanisms at the BBB may compromise the therapeutic index in the target brain region. Additionally, efflux transport proteins such as Pgp and BCRP were also found to be significantly upregulated in human epileptic brain regions versus non-epileptic regions, suggesting an increased efflux of anti-seizure medications under the diseased condition in accordance with the transporter hypothesis of refractory epilepsy [ 58 , 59 ]. More recently, the relevance of upstream molecular regulators/transcription factors such as glucocorticoid receptors (GR) and pregnane X receptors (PXR) and their control of drug metabolizing enzymes and drug transporters has been noted in the human epileptic brain, especially at BBB endothelial cells [ 60 , 61 , 62 ].…”

Section: Common Methods To Treat Selective Central Nervous System Disordersmentioning

confidence: 92%

Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

2021

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Due to the physiological and structural properties of the blood–brain barrier (BBB), the delivery of drugs to the brain poses a unique challenge in patients with central nervous system (CNS) disorders. Several strategies have been investigated to circumvent the barrier for CNS therapeutics such as in epilepsy, stroke, brain cancer and traumatic brain injury. In this review, we summarize current and novel routes of drug interventions, discuss pharmacokinetics and pharmacodynamics at the neurovascular interface, and propose additional factors that may influence drug delivery. At present, both technological and mechanistic tools are devised to assist in overcoming the BBB for more efficient and improved drug bioavailability in the treatment of clinically devastating brain disorders.

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Section: Common Methods To Treat Selective Central Nervous System Disordersmentioning

confidence: 92%

Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

2021

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“…Overexpression of CYP3A4 protein was found in primary endothelial cells established from brain specimens from drug-resistant epileptic patients ( Ghosh et al, 2010 ). Data on brain specimens surgically resected from patients with epilepsy also showed that the protein level and activity of CYP3A4 in the brain region of epilepsy lesions were significantly increased compared to non-epileptic regions ( Williams et al, 2019 ). A report explained that overexpression of CYP3A4 had close correlation with pregnane X and glucocorticoid receptors in endothelial cells from epileptic patients ( Ghosh et al, 2017 ).…”

Section: Alterations In Expressions and Functions Of Cytochrome P450s And Udp-glucuronosyltransferases Under Diseases And Their Impacts Omentioning

confidence: 99%

“…Quinolinic acid was also detected in brain of epileptic patients receiving carbamazepine, but not in epileptic patients receiving other antiepileptics or control patients ( Ghosh et al, 2012 ). In addition, administration of antiepileptics metabolized by CYPs increased CYP3A4 protein level in both epileptic and non-epileptic brain regions of epileptic patients, then enhancing metabolism of drugs in brain and aggravating drug resistance ( Williams et al, 2019 ). Overall, abnormal elevation of CYP3A4 under epilepsy has pathological relevance to the mechanism of drug-resistance epilepsy.…”

Section: Alterations In Expressions and Functions Of Cytochrome P450s And Udp-glucuronosyltransferases Under Diseases And Their Impacts Omentioning

confidence: 99%

“…Epilepsy is a common chronic CNS disease, in which the sudden abnormal discharge of brain neurons leads to transient brain dysfunction. Several investigations have demonstrated that epilepsy altered expressions and functions of drug transporters (Luna-Tortós et al, 2010;Ma et al, 2013;Sun et al, 2016) and enzymes (Ghosh et al, 2010;Williams et al, 2019) in BBB and brain, which affects the bioavailability of antiepileptics through BBB, leading to pharmacoresistance.…”

Section: Epilepsy and Drug Resistancementioning

confidence: 99%

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Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

Yun

Yang

et al. 2021

Front. Pharmacol.

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Cytochrome P450s (CYPs) and UDP-glucuronosyltransferases (UGTs) are both greatly important metabolic enzymes in various tissues, including brain. Although expressions of brain CYPs and UGTs and their contributions to drug disposition are much less than liver, both CYPs and UGTs also mediate metabolism of endogenous substances including dopamine and serotonin as well as some drugs such as morphine in brain, demonstrating their important roles in maintenance of brain homeostasis or pharmacological activity of drugs. Some diseases such as epilepsy, Parkinson’s disease and Alzheimer’s disease are often associated with the alterations of CYPs and UGTs in brain, which may be involved in processes of these diseases via disturbing metabolism of endogenous substances or resisting drugs. This article reviewed the alterations of CYPs and UGTs in brain, the effects on endogenous substances and drugs and their clinical significances. Understanding the roles of CYPs and UGTs in brain provides some new strategies for the treatment of central nervous system diseases.

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“…Quantifications of the immunostaining (n = 20/subject) were performed using ImageJ software (National Institutes of Health) as previously described [26]. Background was removed using the brightness and contrast controls and the Rolling Ball Radius function.…”

Section: Immunofluorescence Stainingmentioning

confidence: 99%

Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resistant Epilepsy

et al. 2020

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Pharmacoresistance in epilepsy is a major challenge to successful clinical therapy. Glucocorticoid receptor (GR) dysregulation can affect the underlying disease pathogenesis. We recently reported that local drug biotransformation at the blood-brain barrier is upregulated by GR, which controls drug-metabolizing enzymes (e.g., cytochrome P450s, CYPs) and efflux drug transporters (MDR1) in human epileptic brain endothelial cells (EPI-ECs). Here we establish that this mechanism is influenced upstream by GR and its association with heat shock proteins/co-chaperones (Hsps) during maturation, which differentially affect human epileptic (EPI) tissue and brain endothelial cells. Overexpressed GR, Hsp90, Hsp70, Hsp40 were found in EPI vs. NON-EPI brain regions. Elevated neurovascular GR expression and co-localization with Hsps was evident in the EPI regions with cortical dysplasia, predominantly in the brain micro-capillaries and neurons. A corresponding increase in ATPase activity (*p < 0.05) was found in the EPI regions. The GR-Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1 *

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Neurovascular Drug Biotransformation Machinery in Focal Human Epilepsies: Brain CYP3A4 Correlates with Seizure Frequency and Antiepileptic Drug Therapy

Cited by 16 publications

References 45 publications

Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

Drug Delivery Challenges in Brain Disorders across the Blood–Brain Barrier: Novel Methods and Future Considerations for Improved Therapy

Alterations of Cytochrome P450s and UDP-Glucuronosyltransferases in Brain Under Diseases and Their Clinical Significances

Heat Shock Proteins Accelerate the Maturation of Brain Endothelial Cell Glucocorticoid Receptor in Focal Human Drug-Resistant Epilepsy

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