Clinical and Genetic Aspects of Epilepsy by Z. Afawi

By Z. Afawi

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Thus, since potent and specific inhibitors that can be safely given to patients are currently not available, transporter inhibition does not seem to be a viable treatment option in drug-resistant epilepsy at this point in time. 2 Modulation of transporter regulation Targeting signalling pathways that regulate drug efflux transporters is another strategy to overcome transporter-mediated AED resistance. The advantages of this approach are threefold. First, modulating transporter regulation to increase AED brain delivery may allow fine tuning of the transporter.

These findings support the idea of dynamic CYP regulation at the blood-brain barrier by AED exposure. In general, regulation of CYPs at the blood-brain barrier could be independent from that in the liver. Support for this comes from studies in alcoholics. , 2010; Miksys & Tyndale, 2004). , 2010). Nuclear receptors that act as transcription factors control regulation of CYPs and ABC transporters in the CNS. , 2004). For example, Dauchy et al. , 2008). , 2010). This idea is supported by the fact that metabolites of CYP2J2, which is expressed in brain endothelial cells in epilepsy, activate the nuclear receptors PPAR-α (NR1C1) and PPAR-γ (NR1C3).

2. Metabolic Enzymes The concept of a “metabolic barrier” is widely accepted but little information is available on metabolising enzymes at the blood-brain barrier. Early studies focused on phase I enzymes in whole brain tissue but later studies differentiated between different brain cell types. Walther et al. showed that CYP P450 enzymes are located in the inner mitochondrial membrane of neurons and glia from rat, guinea pig, rabbit, and pig brain. , 1986). Consistent with this, Ghersi-Egea et al.

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