Abstract
NMDA receptor (NMDAR) is known for its ionotropic function. But recent evidence suggests that NMDAR also has a non-ionotropic property. To determine the role of non-ionotropic activity of NMDARs in clinical relevant conditions, we tested the effect of glycine, a co-agonist of NMDARs, in rat middle cerebral artery occlusion (MCAO), an animal model of cerebral ischemia-reperfusion injury after the animals were injected with the NMDAR channel blocker MK-801 and the glycine receptor antagonist strychnine. We show that glycine reduces the infarct volume in the brain of ischemic stroke animals pre-injected with MK-801 and strychnine. The effect of glycine is sensitive to the antagonist of glycine-GluN1 binding site and blocked by Akt inhibition. In the neurobehavioral tests, glycine improves the functional recovery of stroke animals pre-injected with MK-801 and strychnine. This study suggests that glycine-induced neuroprotection is mediated in part by the non-ionotropic activity of NMDARs via Akt activation in cerebral ischemia-reperfusion injury.
Highlights
The ionotropic glutamate receptors mediate the vast majority of excitatory neurotransmission in the mammalian central nervous system (CNS)[1, 2]
As glutamate-induced neurotoxicity plays critical role in many neurological disorders including ischemic stroke, in the present study we tested the effect of glycine in rat middle cerebral artery occlusion (MCAO)[17, 18], an animal model of cerebral ischemia-reperfusion injury after the animals were injected with the NMDA receptor (NMDAR) channel blocker MK-801 and the glycine receptor antagonist strychnine
We demonstrate that glycine treatment reduces the infarct volume and improves the functional recovery of stroke animals, suggesting that glycine-induced neuroprotection is mediated in part by the non-ionotropic activity of NMDARs in cerebral ischemia-reperfusion injury
Summary
Glycine protects against ischemia-reperfusion injury through non-ionotropic activity of NMDARs. Our data showed that compared with rats treated with strychnine and MK-801 treatment (I/R + Stry + MK group), rats treated with glycine (I/R + Stry + MK + Gly group) had significantly lower scores of mNSS test at day 7 and 14 after MCAO (Fig. 5A), lower scores of beam-walking test at day 3, 7 and 14 after MCAO (Fig. 5B), and higher ratio of MST test at day 7 and 14 after MCAO (Fig. 5C) These results provide functional evidence for the role of non-ionotropic activity of NMDARs in mediating the neuroprotective effect of glycine. To determine whether glycine-GluN1 binding mediates glycine-induced functional recovery in the ischemic stroke animals, in the same experimental conditions, L-689560 (0.1 mg/100 g, ip) was injected with MK-801 (8.0 μg/100 g) and strychnine (1.2 μg/100 g) at 30 min prior to glycine treatment. These results support the conclusion that glycine triggers a non-ionotropic activation of NMDARs and induces a functional recovery in ischemic stroke animals via Akt activation
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