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  • br Evasion strategies for enhanced therapeutic outcomes In


    Evasion strategies for enhanced therapeutic outcomes In order to increase AED penetration into the CNS, several strategies have been developed over the years to overcome the activity of efflux transporters, by inhibiting their function or by regulating their expression. Due to the high relevance of ABCB1 and the low amount of studies in other ABC transporters, the evasion strategies herein mentioned will mainly focus on ABCB1. In this section, three different strategies will be focused: inhibition of efflux transporters; down-regulation of ABC transporters expression through RNA interference; and targeting key modulators of inflammation and seizure-mediated signalling (Fig. 2). Other evasion strategies not addressed in this review include approaches that directly bypass the BBB, without exposing AEDs to the action of efflux transporters. These include encapsulation of therapeutic drugs in drug delivery systems, such as liposomes and polymeric nanoparticles, that readily cross the BBB [165]. Intravenous injection of poly-lactic-co-glycolic N-Methyl-D-aspartic acid (PLGA) nanoparticles loaded with carbamazepine was shown to increase its anticonvulsive effect by 30-fold compared to the free drug, and Abcb1 inhibition had no effect on the responsiveness to this drug [166], demonstrating that this delivery system keeps carbamazepine away from efflux transport. Encapsulation of lamotrigine in polymeric micelles was also shown to increase lamotrigine brain-to-plasma ratio, particularly in regions that overexpressed Abcb1 (cerebrum and hippocampus) in the pilocarpine rat model of epilepsy [167]. Other delivery routes include intranasal administration, to directly deliver AEDs to the brain and circumvent the BBB [168]. Nanoparticle-based delivery or free delivery of carbamazepine were shown to enhance its brain bioavailability [169,170], representing a promising alternative route for treating DRE.
    Conclusion One of the weakest pillars in the transporter hypothesis concerns the proof that marketed AEDs are indeed substrates of ABC transporters and whether this transport is clinically relevant. In fact, we only substantiate lamotrigine, phenobarbital and lamotrigine as definitive ABCB1 substrates. Carbamazepine, levetiracetam and topiramate are also possible substrates of this transporter. For ABCCs and ABCG2 evidence is still required, although few in vivo experiments suggest carbamazepine and phenytoin are transported by members of the ABCC family. As herein emphasized, the lack of evidence does not necessarily mean that AEDs are not substrates of ABC efflux transporters, considering the aforementioned methodological difficulties and the fact that AEDs are highly permeable and weak substrates of these transporters. In this context, imaging techniques like PET will allow to answer these questions and clarify the brain structures that upregulate efflux transporters.
    Conflicts of Interest
    Acknowledgements This work was financed by FEDER funds through Portugal2020 in the scope of the Operational Programme for Competitiviness and Internationalisation, and Fundação para a Ciência e Tecnologia (FCT), Portuguese Agency for Scientific Research, within the scope of the research project POCI-01-0145-FEDER-030478.
    Glutamate Glu is present in high concentrations in practically all of the brain areas and its receptors are widely distributed and expressed in neuronal and non-neuronal cells. This excitatory amino acid plays an important role in higher brain functions such as cognition, learning and memory formation (Birur et al., 2017, Fonnum, 1984, Headley and Grillner, 1990, Stanley et al., 2017), as well as in other plastic changes involved in the regulation of CNS development like synapse induction and elimination (Durand et al., 1996, Murphy-Royal et al., 2015, Rabacchi et al., 1992), and cell migration and differentiation (Campana et al., 2017, Komuro and Rakic, 1993, Rossi and Slater, 1993, Song et al., 2017). Glu concentration in the synaptic space is in the low micromolar range (3–4 μM) and around 10 μM in the extracellular fluid and in the cerebrospinal fluid (Danbolt, 2001, Hamberger and Nystrom, 1984, Lehmann et al., 1983).