Glycine is required for NMDA receptor activation: electrophysiological evidence from intact rat hippocampus

Effect of ginkgolide B on striatal extracellular amino acids in middle cerebral artery occluded rats

“…Then a cascade of events will lead to cell death (Rothman and Olney, 1987;Choi et al, 1988;Butcher et al, 1990;Small and Buchan, 1996). Glycine in the cerebrum is an important facilitator of Glu's action through an allosteric site on the NMDA receptor (Kleckner and Dingledine, 1988;Dalkara et al, 1992;Heurteaux et al, 2006). Glycine is also increased after cerebral ischemia (Baker et al, 1991;Masaya et al, 2007).…”

A Glycine Site Antagonist, ZD9379, Reduces Number of Spreading Depressions and Infarct Size in Rats With Permanent Middle Cerebral Artery Occlusion

“…16 For the NMDA ionophore to become permeable to calcium, a recognition site for glycine must be occupied simultaneously with the glutamate binding at the NMDA receptor. 35,36 The mechanism whereby NMDA receptor antagonists prevent the elicitation of SD most probably resides in their prevention of glutamate binding to the receptor protein or to the blockade of the receptor-coupled ionophore. 34 Hypothermia can reduce or even completely inhibit the release of glutamate 37 and can abolish SD.…”

Neuroprotective Effect of NMDA Receptor Glycine Recognition Site Antagonism Persists When Brain Temperature is Controlled

“…Tem p erature is Controlled *Seiji Takaoka, tRobert D. Bart, +Robert Pearlstein, §Ann Brinkhous, and §David S. Warner During MCAO and the first 24 h of reperfusion, rats (n = 10) were administered either vehicle or the glycine an tagonist 5-nitro-6,7-dichloro-2,3-quinoxalinedione (ACEA 1021) i,v, as a bolus infusion of 5 mg/kg followed by 3,5 mg/kg/h (Low-Dose) or 10 mg/kg followed by 7 mg/kg/ A theoretical pharmacologic approach to amelio ration of ischemic brain damage is antagonism of the glycine recognition site of the N-methyl-o-aspartate (NMDA) receptor complex, Glycine and glutamate are required to co-activate the NMDA receptor be fore the associated ionophore becomes permeable to calcium (Dalkara et al, 1992;Forsythe et al, 1988;Lester et al, 1993). Glycine has also been demon-h (High-Dose) for 24 h, Cortical temperature was con trolled at 38,0 ± 0,1 DC during MCAO and the first 6 h of reperfusion, A 7-day recovery interval was allowed, Mean total infarct volume was reduced by -40% in both high and low-dose groups (p < 0.01), The preponderance of infarct reduction occurred in the cortex (p < 0,01), Neuro logic function correlated with the size of cerebral infarct (p = 0,001), Neurologic grade was similarly improved by treatment with either dose (p = 0,01), These results demon strate that neuroprotection achieved by antagonism of the glycine recognition site persists when brain temperature is controlled, indicating a potent mechanism of action other than attenuating a hyperthermic response to ischemia, Key Words: NMDA-Glycine antagonists-Neuroprotec tion-Brain temperature-Ischemia, strated to potentiate glutamate toxicity in cultured neurons (Johnson and Ascher, 1987).…”