The dynamics of excitatory (glutamate, aspartate) and inhibitory (GABA, glycine) neurotransmitter amino acid contents in the cerebrospinal fluid were studied in 110 patients with hemispheric ischemic insult. These studies revealed significant increases in the levels of glutamate and aspartate in the first six hours of illness, and the level and duration of these changes correlated with the severity of the insult. Peak GABA and glycine levels were seen at the end of the first day after strokes, reflecting the delayed activation of the mechanisms of protective inhibition. The insufficiency of GABAergic mediation in strokes located in the hemispheres to a significant extent mirrored the severity of clinical features and the potential of restorative processes. Early significant biochemical criteria were identified for objective assessment of the severity of brain ischemia, and these had pronostic value for the course and outcome of strokes. The most unfavorable prognostic signs were the presence of low (or undetectable) GABA levels in the first days after insult and progressive increases in aspartate levels to the third day on the background of sharp reductions in glutamate levels (after initial elevation on the first day).

The aim of this randomized, double-blind, placebo-controlled trial was to assess the safety and the efficacy of the pharmaceutic drug glycine in 200 patients with acute (<6 h) ischaemic stroke in the carotid artery territory. Fifty patients received placebo, 49 glycine 0.5 g/day, 51 glycine 1.0 g/day and 50 glycine 2.0 g/day for 5 days in each group. The efficacy of glycine was assessed by clinical analysis, by an enzyme-linked immunosorbent assay of levels of blood serum autoantibodies to NMDA-binding proteines, by detection of excitatory (glutamate, aspartate) and inhibitory (glycine, GABA) amino acid concentrations and lipid peroxidation products (TBARS) in CSF. The trial confirmed the safety profile of the glycine treatment. Slight sedation was observed in 9 patients (4.5%) as a side-effect. Other marked side-effects or adverse events were absent. The glycine treatment at the dose of 1.0–2.0 g/day was accompanied by a tendency to a decreased 30-day mortality (5.9% in 1.0 g/day glycine and 10% in 2.0 g/day glycine groups vs. 14% in the placebo and 14.3% in 0.5 g/day glycine groups), to an improved clinical outcome on the Orgogozo Stroke Scale (p < 0.01) and the Scandinavian Stroke Scale (p < 0.01) and to a favourable functional outcome on the Barthel index (p < 0.01 in 1.0 g/day glycine vs. placebo group in patients with no or mild disability). An early normalization of autoantibody titres to NMDA-binding proteins in serum was found (p < 0.01 vs. placebo), a reduction of glutamate and aspartate levels (p < 0.05 vs. placebo), an increase in GABA concentrations (p < 0.01 vs. placebo in severe stroke patients) and also a reduction of TBARS levels (p < 0.05 vs. placebo) in CSF by day 3. Thus, the trial suggests that sublingual application of 1.0–2.0 g/day glycine started within 6 h after the onset of acute ischaemic stroke in the carotid artery territory is safe and can exert favourable clinical effects. These results will be verified in further trials with a larger number of patients.

The dynamics of the levels of both excitatory (aspartate, glutamate) and inhibitory (GABA, glycine) neurotransmitter amino acids was estimated in cerebrospinal fluid of 110 patients with hemispheric ischemic stroke. A significant increase of the contents of glutamate and aspartate was found begining with the first 6 hours of the disease onset. The degree and duration of such elevation correlated with severity of the stroke. Maximal GABA and glycine levels were registered to the end of the 1st day of the stroke, that reflected delayed triggering of the protective inhibitory mechanisms. It was established that insufficiency of GABA-mediation in hemispherical location of the stroke was much responsible for both the severity of its clinical manifestations and potential of the restorative processes. Early significant biochemical criteria for objective assessment of the severity of cerebral ischemia as well as of the stroke course and outcome were defined. The most unfavourable prognostic signs were low GABA concentration (or impossibility of its evaluation) during the first days of the stroke, progredient elevation of the aspartate level until the 3d day of the disease and the severe fall of glutamate concentration (in spite of its initial increase on the 1st day).

The level of autoantibodies (aAB) to main structural component of glutamate NMDA-receptors--phencyclidin-binding protein--was measured in blood serum of 70 patients during first 3, 6, 9, 12, 24 hours, and 3, 5 days after ischemic stroke development. 200 healthy individuals formed the control group. The elevation of titers of aAB to glutamate receptors was observed in all patients with severe or moderate disease from the very first hours of stroke. It was especially pronounced by 9-12 hours after stroke. The highest increase of aAB titers was found in severe cases. The tendency to normalization of aAB titers was observed by the end of the first twenty four hours. The degree of aAB elevation had the prognostic importance. The most favourable course of stroke with good restoration of damaged functions was predicted when stable normalization of the aAB level was observed by the third day of the disease development. Patients in stupor-coma condition did not show the phenomenon of aAB level's elevation during the first days of stroke, that reflected, probably, the development of immuno-deficient state. The decrease of aAB level down to subnormal values was extremely unfavourable prognostic sign proceeding patient's death as a rule.