Glycine, a simple physiological compound protecting by yet puzzling mechanism(s) against ischaemia-reperfusion injury: current knowledge

Abstract

Ischaemia is amongst the leading causes of death. Despite this importance, there are only a few therapeutic approaches to protect from ischaemia-reperfusion injury (IRI). In experimental studies, the amino acid glycine effectively protected from IRI. In the prevention of IRI by glycine in cells and isolated perfused or cold-stored organs (tissues), direct cytoprotection plays a crucial role, most likely by prevention of the formation of pathological plasma membrane pores. Under in vivo conditions, the mechanism of protection by glycine is less clear, partly due to the physiological presence of the amino acid. Here, inhibition of the inflammatory response in the injured tissue is considered to contribute decisively to the glycine-induced reduction of IRI. However, attenuation of IRI recently achieved in experimental animals by low-dose glycine treatment regimens suggests additional/other (unknown) protective mechanisms. Despite the convincing experimental evidence and the large therapeutic width of glycine, there are only a few clinical trials on the protection from IRI by glycine with ambivalent results. Thus, both the mechanism(s) behind the protection of glycine against IRI in vivo and its true clinical potential remain to be addressed in future experimental studies/clinical trials.

© 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Figures

Figure 1

Glycine and other glycine receptor agonists, antagonists and compounds with low affinity to the glycine receptor. GlyR, glycine receptor.

Figure 2

Metabolism of glycine. THF, tetrahydrofolate.

Figure 3

Glycine, an inhibitory neurotransmitter and an inhibitor of the activation of immune cells. Activation of GlyR by glycine results in influx of chloride ions, membrane hyperpolarization and thus, in neurons, in inhibition of the response to excitatory neurotransmitters. In immune cells, hyperpolarization inhibits opening of voltage-operated calcium channels (VOCs), thus influx of calcium ions and activation of these cells, resulting among others in attenuation of the formation of TNF-α, NO and ROS.

Figure 4

Cell injury, inflammatory response and regeneration during or following ischaemia–reperfusion. Protective effects of glycine. At concentrations around 1 mM and above, glycine decreases hypoxic cell injury by direct cytoprotection and inhibits the inflammatory response. A direct cytoprotective effect of glycine on other forms of cell injury occurring during reperfusion, such as those mediated by ROS, remains a matter of debate. The mechanism of protection by glycine at low-dose treatment regimens is unknown. The same is true for the effect of glycine on regeneration of the tissue injured by ischaemia–reperfusion.

Figure 5

Formation of pathological plasma membrane pores during hypoxic injury and its prevention by glycine. During hypoxic cell injury, pathological pores are formed in the plasma membrane with increasing size. These pores are composed of different proteins, with components of GlyR presumably playing a central role. Glycine prevents the formation of these pores by binding to the GlyR components but possibly also to other structurally related proteins.