Oxidative Stress leads to Glutamate dyshomeostasis

In the central nervous system (CNS), glutamate (Glu) is rapidly taken up at the synaptic cleft to mitigate potential excitotoxicity (Meldrum, 2000). Reuptake is carried out by the electrochemical gradient of Glu across the plasma membrane and is accomplished by Glu transporter proteins, referred to as excitatory amino acid transporters (EAATs). These transporter proteins are predominantly expressed in astrocytes, but they are also be found in other neural cells, such as oligodendrocyte, neuron, and microglia membranes (Danbolt, 2001). Functional Glu transporters are located on cell surface membranes. The activities of these transporters are regulated by a redistribution of these proteins to or from the plasma membrane (Robinson 2002), under the control of several signaling pathways. Five different families of EAATs have been recognized (EAAT1–EAAT5). They vary in Na⁺ and/or K⁺ coupling abilities. Their names differ based on the presence of the transporter in human or in other mammals (see Table 1).

Table 1: Glu transporters in human and mammals and their occurrence in CNS cells. From Rajda et al., 2017

These transporters co-localize with, form physical (co-immunoprecipitable) interactions with, and functionally couple to various 'energy-generating' systems, including the Na(+)/K(+)-ATPase, the Na⁺/Ca²⁺ exchanger, glycogen metabolizing enzymes, glycolytic enzymes, and mitochondria/mitochondrial proteins. This functional coupling is bi-directional with many of these systems both being regulated by glutamate transport and providing the 'fuel' to support glutamate uptake (Robinson and Jackson, 2016). The Na⁺ gradient, which depends on Na/K ATPase pump and consequently of ATP production and intracellular levels, provides the energy to move Glu from the outside into the cells, accompanied by two Na⁺ and an H⁺ ; at the same time, K⁺ moves in the opposite direction (Boron and Boulpaep, 2003). Mitochondrial dysfunction leads to a decrease in ATP synthesis, impaired Ca²⁺ content, and concomitant increase in the levels of ROS (Reactive Oxygen Species) and RNS (Reactive Nitrogen Species) (Beal, 2005). Free radicals, which are electrically unstable, have a central role in several physiological and pathological processes. Both ROS and RNS originate from endogenous and exogenous sources. Mitochondria, endoplasmic reticulum, peroxisomes, phagocytic cells, and others serve as endogenous sources, and environmental factors, such as alcohol, tobacco, pollution, industrial solvents, pesticides, heavy metals, specified medicines, etc. make up the prepondarance of exogenous factors. Significant amounts of reactive oxygen species (ROS) and reactive nitrogen species (RNS,) are formed during oxidative phosphorylation, when the greatest amount of ATP is produced. Cellular antioxidants production serves as a countermeasure against this process (Su et al., 2013; Szalardi et al., 2015). Most cells, including astrocytes, have protective mechanisms against ROS, predominantly in the form of the tripeptide thiol, glutathione (GSH) (Hsie et al., 1996). This process stays in a highly sensitive balance. In the specific case when ROS and RNS synthesis exceeds antioxidant synthesis it results in oxidative stress (Reddy, 2006; Ghafouribar et al., 2008; Su et al., 2013; Szalardi et al., 2015; Valko et al., 2007; Yankovskaya et al., 2003; Senoo-Matsuda et al., 2003;  Schon and Manfredi, 2003).

According to Porciuncula et al., (2003), a decrease of 50% of H⁺-ATP activity was associated to a decrease of 50% of glutamate uptake following exposure of synaptic vesicles with 5 uM of methylmercury.

Xu et al. (2012) and Feng et al. (2014) observed that in rats treated with 12 umoles/kg for 4 weeks a 4-fold increase in ROS level in cerebral cortex, and a 2-fold increase in protein and DNA peroxidation were associated with about 20% increase of glutamate and 30% decrease of glutamine.

Experimental evidences has been observed mainly in rodent, but due to occurrence of oxidative stress and the presence of glutamate in different taxa, it may be much broader, as suggested by similar observations in C. elegans (Wu et al., 2015).