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

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Abstract

Pharmacoresistance is a major clinical challenge for approximately 30% of patients with epilepsy. Previous studies indicate nuclear receptors (NRs), drug efflux transporters, and cytochrome P450 enzymes (CYPs) control drug passage across the blood-brain barrier (BBB) in drug-resistant epilepsy. Here, we (1) evaluate BBB changes, neurovascular nuclear receptors, and drug transporters in lesional/epileptic (EPI) and non-lesional/non-epileptic (NON-EPI) regions of the same brain, (2) examine regional CYP expression and activity, and (3) investigate the association among CYP brain expression, seizure frequency, duration of epilepsy, and antiepileptic drug (AED) combination. We used surgically resected brain specimens from patients with medically intractable epilepsy (n = 22) where the epileptogenic loci were well-characterized by invasive and non-invasive methods; histology confirmed distinction of small NON-EPI regions from EPI tissues. NRs, transporters, CYPs, and tight-junction proteins were assessed by western blots/immunohistochemistry, and CYP metabolic activity was determined and compared. The relationship of CYP expression with seizure frequency, duration of epilepsy, and prescribed AEDs was evaluated. Decreased BBB tight-junction proteins accompanied IgG leakage in EPI regions and correlated with upregulated NR and efflux transporter levels. CYP expression and activity significantly increased in EPI compared to NON-EPI tissues. Change in EPI and NON-EPI CYP3A4 expression increased in patients taking AEDs that were CYP substrates, was downregulated when CYP- and non-CYP-substrate AEDs were given together, and correlated with seizure frequency. Our studies suggest focal neurovascular CYP-NR-transporter alterations, as demonstrated by the relationship of seizure frequency and AED combination to brain CYP3A4, might together impact biotransformation machinery of human pharmacoresistant epilepsy.

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Acknowledgments

This work was supported in part by grants R01NS078307 and R01NS095825 from the National Institute of Neurological Disorders and Stroke/National Institutes of Health and by grants awarded from the Brain and Behavior Research Foundation (formerly NARSAD), the American Heart Association (13SDG13950015), and Alternatives Research & Development Foundation. We would like to acknowledge Saurabh Mishra for initial assistance with western blot.

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Authors and Affiliations

  1. Cerebrovascular Research Laboratory, Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA

    Sherice Williams, Mohammed Hossain & Chaitali Ghosh

  2. Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA

    Lisa Ferguson, Robyn M. Busch, Jorge Gonzalez-Martinez & Imad M. Najm

  3. Cerebrovascular Mechanisms of Brain Disorders Laboratory, Department of Neuroscience, Institute of Functional Genomics (CNRS-INSERM), University of Montpellier, Montpellier, France

    Nicola Marchi

  4. Department of Internal Medicine and Therapeutics, University of Pavia, Clinical Trial Center, IRCCS Mondino Foundation, Pavia, Italy

    Emilio Perucca

  5. Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, OH, USA

    Chaitali Ghosh

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  1. Sherice Williams
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  3. Lisa Ferguson
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Contributions

C.G. designed the experiments and wrote the manuscript. S.W. and M.H. performed the work. C.G., S.W., M.H., N.M., E.P., and I.N. analyzed the data. L.F., I.N., J.G.M. and R.B., helped in tissue procurement. All authors contributed to editing the manuscript.

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Correspondence to Chaitali Ghosh.

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Conflict of Interest

J.G.M. has conflict of interest with Zimmer Biomet, Cleveland. I.N. serves on the Speaker’ bureau and as a member of ad hoc advisory board for Eisai, Inc. E.P. received speaker’s or consultancy fees from Axovant, Biogen, Eisai, GW Pharma, Sanofi, Takeda, UCB Pharma and Xenon Pharma. None of the other authors has any potential conflict of interest to disclose. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Williams, S., Hossain, M., Ferguson, L. et al. Neurovascular Drug Biotransformation Machinery in Focal Human Epilepsies: Brain CYP3A4 Correlates with Seizure Frequency and Antiepileptic Drug Therapy. Mol Neurobiol 56, 8392–8407 (2019). https://doi.org/10.1007/s12035-019-01673-y

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