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  • br Acknowledgments This work was financially

    2021-12-08


    Acknowledgments This work was financially supported by the National Natural Science Foundation of China (No. 81703451) and the China Postdoctoral Science Foundation Grant (No. 2017M611269).
    Introduction According to the International League Against Epilepsy (ILAE), epilepsy is generally defined as a PLX7904 mg disorder characterized by at least two unprovoked (or reflex) seizures apart from each other for not less than 24 h [1]. Epilepsy affects around 50 million people worldwide, with a higher prevalence in resource-poor countries, making it one of the most common neurological diseases, according to the World Health Organization (WHO) [2]. Despite the antiepileptic drugs (AEDs) available in clinical practice, approximately one third of patients with epilepsy remain refractory to treatment [3]. This clinical situation is usually referred to as “drug-resistant”, “pharmacoresistant”, “refractory” or “intractable” epilepsy, and is defined as the failure of two rationally chosen AED used in appropriate dosage schedules, in monotherapy or in combination with other AEDs, to achieve seizure control or freedom [4]. Patients fail to attain a seizure free lifestyle, which highly increases morbidity and mortality, rushing the need to discover the mechanisms underlying drug-resistant epilepsy (DRE) and find effective treatments to avoid seizures [5]. In this regard, there are numerous theories that attempt to explain DRE [6]. Among them emerges the pharmacokinetics hypothesis, which states that efflux transporters located in peripheral organs reduce the systemic bioavailability of AEDs and consequently the concentration available to cross the blood-brain barrier (BBB) and reach the biophase [7]. Complementarily, the transporter hypothesis emphasises that those efflux PLX7904 mg transporters are overexpressed in endothelial cells of BBB and in other cells of epileptic brain, hampering the AEDs access into the central nervous system (CNS) and decreasing the concentration of the AEDs in the epileptogenic tissue [8]. In parallel, the neuronal network hypothesis and the intrinsic severity hypothesis are also gaining force, with the former claiming that seizure activity is responsible for the remodelling and degeneration of the neuronal structure and therefore restrains AEDs from reaching neuronal targets [9], while the second proposes that drug-resistance is due to the intrinsic pathophysiological evolution of epilepsy [10]. More recently, the gene variant hypothesis started to postulate that drug resistance results from genetic variations that occur in pharmacodynamic targets of AEDs (such as voltage-gated Na+ channels) and in crucial biomolecules that determine AEDs pharmacokinetics, namely enzymes from the cytochrome P450 (CYP) superfamily [11]. Similarly, the target hypothesis also states that modifications in AED target receptors causes unresponsiveness to their action [12]. DRE has certainly a multifactorial explanation, considering that each individual theory cannot fully explain refractoriness to treatment [6].
    The blood-brain barrier and the role of efflux transporters in epilepsy The BBB is a vital physiological interface responsible for protecting the CNS and regulate its narrow homeostatic state. The BBB controls the exchange of molecules, ions and cells between the blood and the CNS [13]. Its restrictive action is partially explained by the continuous non-fenestrated capillaries that compose its microvasculature [14]. The neurovascular unit of the BBB is composed by different cells: endothelial cells, connected to each other by tight junctions and adherens junctions; pericytes; astrocytes, which form the astrocytic endfoot processes; the free microglia that plays a central role in the innate and adaptive immune responses of the CNS; and neurons [15]. In epilepsy, as a result of consecutive and successive seizures, the physiological function of the BBB is disrupted, with upregulation of leukocyte adhesion molecules in the microvascular endothelial cells that stimulate immune cell trafficking, causing inflammation and BBB leakage [16]. Recent findings also point out that neurovascular events go beyond the leakage of the BBB, but also concern abnormal interstitial fluid in epileptogenic areas that favours the accumulation of serum proteins, namely albumin and immunoglobulin G, in the perivascular space of the brain [17].