Nucleic Acid Aptamers for Molecular Therapy of Epilepsy and Blood-Brain Barrier Damages

Abstract

Epilepsy is the fourth most prevalent brain disorder affecting millions of people of all ages. Epilepsy is divided into six categories different in etiology and molecular mechanisms; however, their common denominator is the inability to maintain ionic homeostasis. Antiepileptic drugs have a broad spectrum of action and high toxicity to the whole organism. In many cases, they could not penetrate the blood-brain barrier (BBB) and reach corresponding targets. Nucleic acid aptamers are a new and promising class of antiepileptic drugs as they are non-toxic, specific, and able to regulate the permeability of ion channels or inhibit inflammatory proteins. In this review, we summarize the mechanisms of epileptogenesis and its interconnection with the BBB and show the potential of aptamers for antiepileptic treatment.

Figure 1

Mechanisms for Maintaining Ionic Homeostasis in Neurons 1, Na⁺/Ca²⁺ exchanger (NCX). 2, Na⁺ and K⁺ pump. 3, Ca²⁺ pump. 4, voltage-gated calcium channel (VGCC). 5, metabotropic glutamate receptor (mGluR). 6, N-methyl-D-aspartate receptor (NMDA-R). 7, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R). 8, acetylcholine receptor (Ach-R). 9, transient receptor potential channel (TRCP). 10, gamma-aminobutyric acid receptor (GABA-R).

Figure 2

Blood-Brain Barrier in Epilepsy (A–F) Disruption of the BBB induces blood cells to enter the brain (A); leukocytes cause inflammation, secrete histamine (B), and activate microglia and astrocytes (C); activated microglia and astrocytes increase inflammation (D), activate metalloproteinase MMP-9 (E), and increase the BBB permeability (F). (G and H) Disruption increases the content of intracellular potassium (G) and glutamate (H) ions. (I) Disruption increases the entry of albumin into the brain, absorbed by neurons and astrocytes through TGF-β receptors, as a result of which Kir 4.1 permeability of potassium channels in astrocytes is reduced. Systemic inflammatory disorders cause an accumulation of inflammatory mediators and contribute to the destruction of the BBB. All processes together increase the excitability of neurons and stimulate epileptimorphic seizures, and the excessive activation of astrocytes stimulates gliosis.

Figure 3

Existed Aptamers and Their Epilepsy-Related Protein Targets