Figure 1.

Schematic representation of ASD encountering “multiple hurdles” to reach the target human regions in pharmacoresistant epilepsy with specific relevance of the BBB.

(A) The “first passage” of the ASD through the liver is responsible for primary drug metabolism. (B) The BBB epileptic endothelial cells play an important role in the barrier interface that governs physiological and metabolic properties. As demonstrated by the right inset, the interaction of GR and heat shock proteins becomes critical for GR maturation (Hossain et al., 2020). Upon activation, GR is responsible for controlling important downstream events including the function of efflux transporters (Pgp), phase 1 and 2 drug metabolizing enzymes (CYPs, uridine 5′-diphospho-glucuronosyltransferase, etc.), and other nuclear receptors (PXR) that are found to be overactive in epileptic brain endothelial cells. (C) Finally, the ASD that permeates through the BBB reaches the brain parenchyma. The GR-CYP-Pgp drug regulatory mechanism at the BBB endothelial cells may affect the neurons. ASD: Antiseizure drug; BBB: blood-brain barrier; CYP P450: cytochrome P450s; EPI-EC: epileptic brain endothelial cells; GR: glucocorticoid receptor; GRE: glucocorticoid-response element; Hsp: heat shock protein; Pgp: P-glycoprotein.