Glycine bidirectionally regulates ischemic tolerance via different mechanisms including NR2A-dependent CREB phosphorylation

The exact effect of glycine pre-treatment on brain ischemic tolerance (IT) remains quite controversial. The objective of this study was to investigate the potential effects of glycine on IT. We used rat models of both in vitro ischemia (oxygen and glucose deprivation) and in vivo ischemia (transient middle cerebral artery occlusion). Low doses of glycine (L-Gly) significantly decreased hippocampal ischemic LTP (i-LTP), infarct volume, and neurological deficit scores which were administered before ischemia was induced in rats, whereas high doses of glycine exerted deteriorative effects under the same condition. These findings suggested that exogenous glycine may induce IT in a dose-dependent manner. Furthermore, L-Gly-dependent neuronal protection was inversed by L689, a selective NMDAR glycine site antagonist both in vitro (abolished i-LTP depression) and in vivo (increased infarct size reduction), but not glycine receptor (GlyR) inhibitor strychnine. Importantly, L-Gly-induced IT was achieved by NR2A-dependent cAMP-response element binding protein phosphorylation. These data imply that glycine pre-treatment may represent a novel strategy for inducing IT based on synaptic NMDAR-dependent neuronal transmission. A model of glycine induced dose-dependent bidirectional regulations in ischemic tolerance. (a) Under low dose of Gly pre-treatment, glycine induces NMDAR potentiation and CREB-dependent neuroprotection through the NMDAR co-agonist binding site. (b) Under high dose of Gly pre-treatment, the excessive glycine in synaptic cleft can activate neighboring extrasynaptic sites and combine to the GlyRs. Then, the deteriorative effects would be triggered after NMDAR endocytosis and synaptic depression. AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; CREB, cAMP response element-binding protein; Gly, glycine; GlyR, glycine receptor; GlyT1, gycine transportor 1; NMDAR, N-methyl-d-aspartate receptor.