Conflicting Effects of Methylglyoxal and Potential Significance of miRNAs for Seizure Treatment

Abstract

According to an update from the World Health Organization, approximately 50 million people worldwide suffer from epilepsy, and nearly one-third of these individuals are resistant to the currently available antiepileptic drugs, which has resulted in an insistent pursuit of novel strategies for seizure treatment. Recently, methylglyoxal (MG) was demonstrated to serve as a partial agonist of the gamma-aminobutyric acid type A (GABAA) receptor and to play an inhibitory role in epileptic activities. However, MG is also a substrate in the generation of advanced glycation end products (AGEs) that function by activating the receptor of AGEs (RAGE). The AGE/RAGE axis is responsible for the transduction of inflammatory cascades and appears to be an adverse pathway in epilepsy. This study systematically reviewed the significance of GABAergic MG, glyoxalase I (GLO1; responsible for enzymatic catalysis of MG cleavage) and downstream RAGE signaling in epilepsy. This work also discussed the potential of miRNAs that target multiple mRNAs and introduced a preliminary scheme for screening and validating miRNA candidates with the goal of reconciling the conflicting effects of MG for the future development of seizure treatments.

TTC3-Mediated Protein Quality Control, A Potential Mechanism for Cognitive Impairment

“…The NLS is a protein domain and another form of a signaling peptide and can be regarded as the key for the entry of macromolecular proteins into the nucleus (Bange et al 2013 ; Tao et al 2018 ). Numerous studies have shown that NLS signaling abnormalities can affect normal physiological functions in many aspects and are associated with a variety of diseases, including neurodegenerative diseases (Nomura et al 2014 ).…”

Glycolysis-Derived Compounds From Astrocytes That Modulate Synaptic Communication

“…More recently, it has been proposed that MG, at physiological levels (μM), acts as an agonist of the γ-aminobutyric acid type A (GABA A ) receptor and is associated with anxiolytic behavior (Distler et al, 2012) and induction of sleep (Jakubcakova et al, 2013). However, due to the lower levels of MG in the synaptic cleft (compared to those of GABA), it has been proposed that MG has a modulatory effect on GABA A receptors in the extrasynaptic space (Tao et al, 2018).…”