Abstract
Excessive activation of NMDA receptors (NMDARs) is implicated in pathological synaptic plasticity also known as post-ischemic long-term potentiation (i-LTP) which was produced by glutamate mediated excitotoxicity after stroke. In the past decades, many NMDARs inhibitors failed in clinical investigations due to severe psychotomimetic side effects. GLYX-13 is a NMDAR modulator with glycine site partial agonist properties and has potential protective effects on ischemic neuronal death. However, the underlying molecular mechanism of GLYX-13 attenuating the ischemic neuronal damage remains elusive. Our study was conducted to examine the molecular, cellular and behavioral actions of GLYX-13 in stroke, and further characterize the mechanism underlying the neuroprotective actions via modulation of the NMDAR subunit composition. In present study we found that in vitro oxygen-glucose deprivation (OGD) stroke model, GLYX-13 blocked i-LTP and restored the ratio of NR2A/NR2B subunit composition. The glycine site of NMDARs full coagonist D-serine completely blocked the effects of GLYX-13 on i-LTP. Besides, in vivo middle cerebral artery occlusion (MCAO) model, GLYX-13 decreased the cerebral infarct volume and reduced injury of hippocampus. Western analysis showed that GLYX-13 down-regulated the expression of phosphorylated NR2B (Tyr1472) and up-regulated phosphorylated NR2A (Tyr1325). Furthermore, GLYX-13 treatment along with NR2B specific antagonist (Ro256981) failed to exhibit any additional neuro-protective effects, whereas the application of NR2A antagonist (NVP-AAM007) abolished the neuroprotective effects of GLYX-13, which suggested that the protective action of GLYX-13 should be by its regulation of NMDAR subunit components. Our study provides important insights on the potential protective mechanism of GLYX-13 in ischemia and proposes the glycine site of NMDARs as a novel target for developing therapeutic strategies to store synaptic function in stroke.
Highlights
Focal cerebral ischemia is one of the most common reasons of death and disability in middle-aged and elderly people worldwide (Lo, 2014)
Since neuronal death in the brain treatment of GLYX-13 + Ro-2569819 after middle cerebral artery occlusion (MCAO) failed to present additional neuroprotective effect compared to GLYX-13 intervention alone (G + R 17.45 ± 1.442% vs. GLYX-13 17 ± 3.468% n = 6, p > 0.05); by contrast treatment of GLYX-13 + NVP-AAM077 completely reversed the amelioration of cerebral infarction elicited by GLYX-13 (G + N 46.79 ± 4.620% vs. GLYX-13 17 ± 3.468%; Figure 12)
Results suggested that compared with the principal role of NR2B subunits in vitro acute oxygen-glucose deprivation (OGD) model, the dysfunction of NR2A subunits are likely more obvious in vivo a few hours even a few days after stroke
Summary
Focal cerebral ischemia (stroke) is one of the most common reasons of death and disability in middle-aged and elderly people worldwide (Lo, 2014). Delayed and progressive nature of neuronal damage following focal cerebral ischemia points to a significant time window for stroke intervention and emphasizes the importance of ameliorating neuronal damage. It would highlight new therapeutic targets for preventing the progression from ischemia to neuronal death (Lai et al, 2014). Many NMDAR antagonists were investigated in animal experiments and clinical trials in the past couple of years These compounds have failed clinical tests in unexpected way mainly due to the major psychotomimetic side effects such as confusion, paranoia, depression and amnesia in subjects, and prevalence of neurological functions require these NMDARs as well
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