**5. Participation in development of pathological processes**

Despite their obvious physiological roles in protein synthesis, the cellular effects of glycine and glutamate in the CNS seem to be quite different. If glycine has been

contemplated an "angel" compound, due to its generally positive effects, then glutamate has usually been considered a "demon" compound, owing to its generally negative effects. Although the last claim is far from accurate, the first is supported by many experimental findings. Indeed, the effect of glycine has always been reported as positive. It protects against oxidative stress caused by a wide variety of chemicals, drugs, and toxicants at the cellular or organ level in the liver, kidneys, intestines, and vascular system [34, 37]. Glycine is a major component of collagen molecules that is vital to stabilizing them to form a triple helix [48]. Administration of glycine attenuates diabetic complications in a streptozotocin-induced diabetic rat model [49]. Supplemental glycine effectively protects muscles in a variety of wasting models, including cancer cachexia, sepsis, and dieting [50]. Glycine may prevent ischaemia–reperfusion injury by direct cytoprotection, presumably by inhibition of the formation of plasma membrane pores and of the inflammatory response [38]. The cytoprotective and modulatory effects of glycine have been observed in many nonneuronal cell types. The action of glycine is mediated by classic or unconventional GlyRs, both inside and outside of the nervous system [51]. Glycine cytoprotection substantially overlaps with the number of agents that act on neuronal receptors with glycine as an agonist or coagonist. This observation has been confirmed by molecular pharmacology studies from multiple laboratories. The studies indicate highly constrained steric and conformational requirements for the interaction, which, along with the rapid on-off timing of the effects, is consistent with the involvement of reversible ligand-binding site interactions [52].

In contrast, glutamate is considered a toxic agent that yields excitotoxicity at overload concentrations. Indeed, the neurotoxic potential of glutamate has been recognized since the 1950s [53]. For example, a major driver of white matter demise is excitotoxicity, a consequence of the excessive glutamate released by vesicular and nonvesicular mechanisms from axons and glial cells. This excessive glutamate concentration results in overactivation of iGluRs profusely expressed by all cell compartments in white matter [54]. Generally, excitotoxicity involves a large inflow of Ca2+ and Na+ into neurons up to the conditions when Ca2+ concentrations reach critical levels, leading to cell injury or death [55]. Moreover, ambient extracellular glutamate is lower than the concentration known to trigger excitotoxicity and subsequent neurodegeneration; excitotoxicity is known to occur at extracellular glutamate concentrations as low as 2 to 5 μM, with swelling and apoptosis predominating at <20 μM glutamate and fast necrosis at >100 μM glutamate [56]. Excitotoxic neuronal death is involved in neurodegenerative diseases of the CNS, such as multiple sclerosis [57], Alzheimer's disease [58], Parkinson's disease [59], Huntington's disease [60], stroke, epilepsy, alcohol withdrawal, and amyotrophic lateral sclerosis [61]. However, the role of glutamate is not only excitotoxic. The assumption that neurodegenerative disease treatments should "fight against" glutamate is incorrect given the wrong function of glutamate in the CNS. As a part of normal physiological excitation, this AA must be properly regulated, but battling with glutamate receptors or the transport system will cause serious negative consequences. Instead, the level and functional activity of glutamate may be adjusted by metabolic processes, including glycine and oxidative phosphorylation, in mitochondria.
