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    • Overall ABC transporters are hypothesised to prevent the

    2022-09-09

    Overall, ABC transporters are hypothesised to prevent the penetration of AEDs and other pharmacological compounds into the brain, being a hurdle for therapeutic delivery in neurological diseases. DRE is thought to be in part related to an increased expression of efflux transporters in the BBB, although the transporters hypothesis cannot fully explain the development of drug resistance [6]. Indeed, seizures and neuronal stress seem to induce the expression and activity of efflux proteins as a defensive pathway to counteract the increased CNS permeability observed during seizures and epilepsy progression [6]. Some studies also corroborate the concept that the chronic use of AEDs may also promote the excessive expression of ABC transporters [52]. These pathophysiological dysfunctions are considerably important for the development of drug resistance, since several AEDs seem to be substrates of ABC transporters. Even though multiple studies have evidenced such correlation throughout the past 20 years, doubts still exist whether multiple AEDs are effectively ABC transporter substrates and if this has real clinical impact. At this point, ABCB1, ABCCs and ABCG2 and their AEDs substrates will be focused on the following sections, given their involvement in DRE.
    Upregulation of ABC transporters in epilepsy Although the overexpression of ABC transporters in epileptic mglur is scientifically supported [98], the challenge is to understand whether this upregulation is caused by the epilepsy progression itself, uncontrolled recurrent seizures, drug-associated induction, genetic polymorphisms or a combination of all these factors [6] (Fig. 1). Another question is whether this upregulation is significant enough to have clinical impact and cause multidrug resistance in epilepsy and other CNS disorders. The first clinical evidence of the transporter theory was postulated by Tishler et al. who found increased levels of ABCB1 mRNA and ABCB1 in brain samples of patients with DRE [99]. Out of 19 brain samples, reverse transcription polymerase chain reaction (RT-PCR) investigations revealed that eleven samples presented levels of ABCB1 mRNA at least 10 times higher than those observed in samples from normal brain; fourteen samples showed an increased staining of ABCB1 in capillary endothelium of epileptic tissue comparing to normal tissue samples [99]. Expression of ABCB1 was also identified in astrocytes of epileptic brain specimens [99]. In another study, which analysed surgically resected brain tissue and post-mortem brain tissue from drug-sensitive and DRE patients, ABCB1 was overexpressed in the epileptogenic hippocampus of DRE patients. This overexpression was only observed for ABCB1, with no significant variations regarding ABCG2 or ABCC1 [100]. The upregulation of ABCB1 was also observed in vivo, by resorting to new imaging techniques such as positron emission tomography (PET), PET and magnetic resonance imaging (PET/MRI). Unlike intracerebral microdialysis, PET can also be applied to humans and allows to measure total tissue distribution of a radiolabelled compound (for a review on the different BBB models see Bicker et al. [101]). These techniques are currently propelling the non-invasive quantitative analysis of live DRE patients, instead of the classical histopathological analysis of surgically resected or post-mortem epileptogenic brain tissue. Their potential regards the identification of the epileptic focus and the anatomical changes that result from seizure activity, helping in DRE diagnosis [102,103]. By administering a radiolabelled ABCB1 substrate, like R-[11C]verapamil, it is possible to study the activity of ABCB1 in vivo, with or without the use of ABCB1 inhibitors [104,105]. Shin et al. performed dynamic R-[11C]verapamil PET/MRI, following cyclosporine A (ABCB1 inhibitor) intravenous infusion, in drug-resistant patients, drug-sensitive patients and healthy subjects [106]. The asymmetry index of the standard uptake of (R)-[11C]verapamil in each of the paired lobes was calculated for the three groups. When the asymmetry index was positive, the standard uptake value of (R)-[11C]verapamil in the left region was lower than that in the right region in each paired lobe. The authors report that patients with DRE had more asymmetry between ipsilateral brain regions of interest and contralateral brain regions than healthy subjects and drug-sensitive patients, which meant the standard uptake of (R)-[11C]verapamil was more asymmetric between these regions in the drug-resistant group. In 3 patients with left temporal lobe DRE, the significantly more positive asymmetry index compared to the healthy subjects was suggestive of ABCB1 overexpression in the left temporal area. Considering the advantages of PET/MRI, this technique might be a useful tool to localize the epileptic focus [106].