Roles of glial ion transporters in brain diseases

Abstract

Glial ion transporters are important in regulation of ionic homeostasis, cell volume, and cellular signal transduction under physiological conditions of the central nervous system (CNS). In response to acute or chronic brain injuries, these ion transporters can be activated and differentially regulate glial functions, which has subsequent impact on brain injury or tissue repair and functional recovery. In this review, we summarized the current knowledge about major glial ion transporters, including Na+/H+ exchangers (NHE), Na+/Ca2+ exchangers (NCX), Na+–K+–Cl− cotransporters (NKCC), and Na+–HCO3− cotransporters (NBC). In acute neurological diseases, such as ischemic stroke and traumatic brain injury (TBI), these ion transporters are rapidly activated and play significant roles in regulation of the intra‐ and extracellular pH, Na+, K+, and Ca2+ homeostasis, synaptic plasticity, and myelin formation. However, overstimulation of these ion transporters can contribute to glial apoptosis, demyelination, inflammation, and excitotoxicity. In chronic brain diseases, such as glioma, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS), glial ion transporters are involved in the glioma Warburg effect, glial activation, neuroinflammation, and neuronal damages. These findings suggest that glial ion transporters are involved in tissue structural and functional restoration, or brain injury and neurological disease development and progression. A better understanding of these ion transporters in acute and chronic neurological diseases will provide insights for their potential as therapeutic targets.

Human umbilical cord mesenchymal stem cell-derived exosomal miR-146a-5p reduces microglial-mediated neuroinflammation via suppression of the IRAK1/TRAF6 signaling pathway after ischemic stroke

“…Apart from recommending follow-up research into the therapeutic potential of cell-free miR-146a-5p in the context of I/R injury and inflammatory disorders, results raise a number of interesting theoretical questions. For example, it is unknown whether hUMSC-Exosomal cargo is also perhaps involved in regulating glial ion transporters (which are involved in the Warburg effect, glial activation, neuroinflammation, and neuronal damage during glioma [ 63 ]). Additionally, might other miRNAs impact microglial function after ischemic stroke?…”

Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke

“…However, under specific conditions such as cerebral ischemia, the expression of NKCCs can be altered [ 94 ]. Overstimulation of NKCC1 and other major glial ion transporters (such as Na + /H + , Na + /Ca 2+ and Na + /HCO 3 − exchangers) can contribute to glial apoptosis, inflammation, demyelination, inflammation, and excitotoxicity [ 26 ]. This cascade of events is involved in the development and progression of neurological diseases such as stroke [ 26 ].…”

“…Overstimulation of NKCC1 and other major glial ion transporters (such as Na + /H + , Na + /Ca 2+ and Na + /HCO 3 − exchangers) can contribute to glial apoptosis, inflammation, demyelination, inflammation, and excitotoxicity [ 26 ]. This cascade of events is involved in the development and progression of neurological diseases such as stroke [ 26 ]. Studies have demonstrated evidence of increase NKCC1 expression in neurons, a phenotype resembling immature neurons, following an ischemic stroke [ 95 , 96 , 97 ].…”

“…Ischemia is the disruption of blood flow and the subsequent depletion of oxygen and glucose. As neuronal components strictly function on aerobic metabolism [ 23 ], an ischemia in the brain leads to reduced available ATP levels and ionic imbalance across the neuronal cell membrane [ 24 ], which causes irreversible neuronal death, also known as ischemic stroke [ 25 , 26 , 27 ]. During this process, an imbalance of excitatory glutamate and inhibitory gamma amino acid butyric acid (GABA) further accelerate neuronal demise [ 28 , 29 , 30 ], subsequently leading to the onset of post-stroke seizures [ 20 , 31 , 32 ].…”

The Therapeutic Potential of Neuronal K-Cl Co-Transporter KCC2 in Huntington’s Disease and Its Comorbidities

“…GABA is the primary neurotransmitter in the SCN [135]; it is the only neurotransmitter that is produced and received by SCN neurons [136]. Furthermore, both GABA A and GABA B receptors are present in more than 90% of SCN neurons [131,135,137,138]. GABA A R activity controls the ability of the pacemaker to shift state in response to light [131,135,139].…”