Possible interplay between the theories of pharmacoresistant epilepsy

Abstract

Epilepsy is one of the oldest known neurological disorders and is characterized by recurrent seizure activity. It has a high incidence rate, affecting a broad demographic in both developed and developing countries. Comorbid conditions are frequent in patients with epilepsy and have detrimental effects on their quality of life. Current management options for epilepsy include the use of anti-epileptic drugs, surgery, or a ketogenic diet. However, more than 30% of patients diagnosed with epilepsy exhibit drug resistance to anti-epileptic drugs. Further, surgery and ketogenic diets do little to alleviate the symptoms of patients with pharmacoresistant epilepsy. Thus, there is an urgent need to understand the underlying mechanisms of pharmacoresistant epilepsy to design newer and more effective anti-epileptic drugs. Several theories of pharmacoresistant epilepsy have been suggested over the years, the most common being the gene variant hypothesis, network hypothesis, multidrug transporter hypothesis, and target hypothesis. In our review, we discuss the main theories of pharmacoresistant epilepsy and highlight a possible interconnection between their mechanisms that could lead to the development of novel therapies for pharmacoresistant epilepsy.

Asociación entre los polimorfismos genéticos de nucleótido único en genes transportadores ABC con la epilepsia farmacorresistente en la población española

“…La explicación plausible de los resultados contradictorios en la bibliografía consultada de los estudios de asociación genética de los genes ABC puede deberse al diseño de los estudios de investigación, que se han realizado con criterios de inclusión y exclusión diferentes, como la falta de la misma definición de epilepsia, la ausencia de homogeneidad en los controles (farmacorrespondedores frente a voluntarios sanos), la heterogeneidad genética y clínica en la epilepsia (diferentes tipos y etiologías), diferentes grupos etarios (adultos frente a pediátricos) y etnias, además de la politerapia en los pacientes con EFR, ya que los múltiples fármacos compiten por la interacción con los transportadores. Asimismo, los factores epigenéticos pueden contribuir por la modificación de histonas y la metilación del ADN [ 44 ].…”

Revisiting the concept of drug‐resistant epilepsy: A TASK1 report of the ILAE/AES Joint Translational Task Force

“…No single theory can explain all cases of DRE. The different hypotheses involve mechanisms that are seen initially as independent, but actually can be linked in many ways 59,106 . For instance, excessive release of glutamate in the brain may contribute to the development of DRE because it contributes to neuronal cell loss and network alterations, 107 to neuroinflammation, 108 and induction of the efflux transporter P‐glycoprotein 84,109 .…”

“…The different hypotheses involve mechanisms that are seen initially as independent, but actually can be linked in many ways. 59,106 For instance, excessive release of glutamate in the brain may contribute to the development of DRE because it contributes to neuronal cell loss and network alterations, 107 to neuroinflammation, 108 and induction of the efflux transporter P-glycoprotein. 84,109 As another example, vascular changes, gliosis, and changes in cerebrospinal fluid dynamics in the seizure-onset zone may all result in reduced (subtherapeutic) ASM concentrations.…”

The Emerging Roles of π Subunit-Containing GABAA Receptors in Different Cancers

“…GABA A Rs vary in their affinity for GABA, expression sites (synaptic or extrasynaptic), and biophysical and pharmacological properties based on their subunit composition. For example, α subtypes have functional variation; α1 results in sedation, whereas α2 and α3 are instrumental in anxiolysis 38 . However, the expression of these subunits is dependent on the other subunits that they co-assemble within the receptor.…”

“…However, the expression of these subunits is dependent on the other subunits that they co-assemble within the receptor. For instance, the α(1/2/3/5) + /γ2 - interface is essential for benzodiazepine-mediated sedation, anxiolysis, seizure suppression, and muscle relaxation 38 , and only the placement of the α subunit next to the γ subunit (α + /γ2 - ) can mediate its function. If both subunits exist within the same receptor but not in the correct order, the resulting GABA A R will not be receptive to benzodiazepine.…”