Our laboratory investigates the role of the blood-brain barrier in health and disease. Our studies focus on cerebrovascular research to better understand brain physiology and function in neurological disorders (e.g., epilepsy and epilepsy with other comorbidities such as stroke, depression). In much of our current work, we investigate the mechanisms and pathophysiological alterations that could possibly impede drug bioavailability across the dysfunctional blood-brain barrier. We study drug-metabolizing enzymes (e.g., cytochrome P450 enzyme, UDP-glucuronosyltransferase); transporters (e.g., P-glycoprotein/MDR1, multidrug resistance-associated proteins); nuclear receptors (e.g., glucocorticoid nuclear receptor, pregnane xenobiotic nuclear receptor), and other regulatory factors that control pharmacokinetic and pharmacodynamic phenomena during drug biotransformation in disease states. With a multidisciplinary team of clinicians, neurosurgeons, and neuroscientists, we investigate the factors contributing to drug resistance in patients suffering from epilepsy. We use multifaceted approaches to test drugs and identify their metabolites. For this, we use a humanized dynamic in vitro neurovascular unit, established with primary brain cells. We simultaneously compare drug metabolite levels in the blood and in resected brain tissue post epilepsy surgery by in situ/ex vivo approaches. Standardized cellular, molecular, immunological, imaging and analytical techniques are followed routinely in the laboratory. The long-term goal of these studies is to develop a screening platform for pharmacological compounds, including drugs across the blood-brain barrier, as a disease-modeling tool to improve drug therapy and to minimize harmful side effects brought on by the interaction of co-prescribed drugs. FUNDING: We thank the National Institutes of Health (NINDS, NCATS), Brain & Behavior Research Foundation (formerly NARSAD), American Heart Association, and Alternatives Research & Development Foundation for their support of this work.
In other words ...
Our laboratory investigates the role of the blood-brain barrier in health and disease.
- Williams, S, Ghosh, C. Neurovascular glucocorticoid receptors and glucocorticoids: implications in health, neurological disorders and drug therapy. Drug Discov Today 2019 Sep 18. pii: S1359-6446(19)30353-8. doi: 10.1016/j.drudis.2019.09.009. [Epub ahead of print]
- Williams, S, Hossain M, Fergusan L, Busch RM, Marchi N, Gonzalez-Martinez J, Perucca E, Najm IM, Ghosh, C. Neurovascular Drug Biotransformation Machinery in Focal Human Epilepsies: Brain CYP3A4 Correlates with Seizure Frequency and Antiepileptic Drug Therapy. Mol Neurobiol. 2019 Dec; 56(12):8392-8407. doi: 10.1007/s12035-019-01673-y.
- Ghosh, C., Hossain M., Mishra S., Sameena K., Gonzalez-Martinez J., Marchi N., Janigro D., Bingaman W., Najm I . Modulation of glucocorticoid receptor in human epileptic endothelial cells impacts drug biotransformation in an in vitro blood‐brain barrier model. Epilepsia. 2018 28. doi: 10.1111/epi.14567. [Epub ahead of print].
- Williams, S., Hossain M., Mishra S., Gonzalez-Martinez J., Najm I., Ghosh, C. Expression and Functional Relevance of Death-Associated Protein Kinase in Human Drug-Resistant Epileptic Brain: Focusing on the Neurovascular Interface. Mol Neurobiol. 2018 Nov 9. doi: 10.1007/s12035-018-1415-z. [Epub ahead of print].
- Ghosh, C., Hossain M., Solanki J., Najm I., Marchi N., Janigro D. Overexpression of Pregnane X and Glucocorticoid receptors and the regulation of cytochrome P450 in human epileptic brain endothelial cells. Epilepsia 2017 Apr;58(4):576-585. doi: 10.1111/epi.13703. Epub 2017 Feb 15. PMID: 28199000.
- Banjara M, Ghosh C. Sterile Neuroinflammation and Strategies for Therapeutic Intervention. Int J Inflam 2017; 2017:8385961. doi: 10.1155/2017/8385961.
- Ghosh C, Hossain M, Solanki J, Dadas A, Marchi N, Janigro D. Pathophysiological implications of neurovascular P450 in brain disorders. Drug Discov Today 2016 Oct; 21(10):1609-1619. doi: 10.1016/j.drudis.2016.06.004.
- Ghosh C, Hossain M, Spriggs A, Ghosh A, Grant GA, Marchi N, Perucca E, Janigro D. Sertraline-induced potentiation of the CYP3A4-dependent neurotoxicity of carbamazepine: an in vitro study. Epilepsia 2015 Mar; 56(3):439-49. doi: 10.1111/epi.12923.
- This article made the cover of the March 2015 issue of Epilepsia.
- This article is highlighted in Nature Reviews Neurology 11, 125 (published online 24 February 2015) http://www.nature.com/nrneurol/journal/vaop/ncurrent/full/nrneurol.2015.22.html
Glucocorticoid receptors (GRs) play a significant role in pharmacoresistant epilepsy and represent a potential therapeutic target, suggests an ongoing line of investigation by Cleveland Clinic researchers.