Cerebral Glutamine and Glutamate Levels in Relation to Compromised Energy Metabolism: A Microdialysis Study in Subarachnoid Hemorrhage Patients

Abstract

Astrocytic glutamate (Glt) uptake keeps brain interstitial Glt levels low. Within the astrocytes Glt is converted to glutamine (Gln), which is released and reconverted to Glt in neurons. The Glt-Gln cycle is energy demanding and impaired energy metabolism has been suggested to cause low interstitial Gln/Glt ratios. Using microdialysis (MD) measurements from visually noninjured cortex in 33 neurointensive care patients with subarachnoid hemorrhage, we have determined how interstitial Glt and Gln, as a reflection of the Glt-Gln cycle turnover, relate to perturbed energy metabolism. A total of 3703 hourly samples were analyzed. The lactate/pyruvate (L/P) ratios correlated to the Gln/Glt ratios (r = À0.66), but this correlation was not stronger than the correlation between L/P and Glt (r = 0.68) or the correlation between lactate and Glt (r = 0.65). A novel observation was a linear relationship between interstitial pyruvate and Gln (r = 0.52). There were 13 periods (404 h) of 'energy crisis', defined by L/P ratios above 40. All were associated with high interstitial Glt levels. Periods with L/P ratios above 40 and low pyruvate levels were associated with decreased interstitial Gln levels, suggesting ischemia and failing astrocytic Gln synthesis. Periods with L/P ratios above 40 and normal or high pyruvate levels were associated with increased interstitial Gln levels, which may represent an astrocytic hyperglycolytic response to high interstitial Glt levels. The results imply that moderately elevated L/P ratios cannot always be interpreted as failing energy metabolism and that interstitial pyruvate levels may discriminate whether or not there is sufficient astrocytic capacity for Glt-Gln cycling in the brain.

Biochemical indications of cerebral ischaemia and mitochondrial dysfunction in severe brain trauma analysed with regard to type of lesion

“…In accordance with recent experimental and clinical studies LP ratio >30 at a pyruvate concentration ≥70 µmol/L was interpreted as a biochemical pattern indicating mitochondrial dysfunction while LP ratio >30 simultaneously with pyruvate <70 µmol/L was interpreted as a biochemical pattern indicating ischemia [8,16,17]. An increase in interstitial glutamate concentration above normal was interpreted as a sign of perturbation of cerebral energy metabolism resulting in impaired astrocytic re-uptake of glutamate [14,24].…”

Hemoglobin Concentration and Cerebral Metabolism in Patients With Aneurysmal Subarachnoid Hemorrhage

“…17,25 An elevated LPR Ͼ40 is considered a marker of cell dysfunction and "energy crisis" secondary to hypoxia/ischemia. 18,27,28 Accordingly, cell energy dysfunction was defined by episodes of elevated LPR Ͼ40 in the cerebral microdialysate. OR and 95% CI for PbtO 2 Ͻ 20 mm Hg and LPR Ͼ40 were adjusted for covariates based on clinical relevance, including CPP, PaO 2 /FiO 2 (P/F) ratio, CVP and presence or absence of symptomatic vasospasm.…”

Measuring multiple neurochemicals and related metabolites in blood and brain of the rhesus monkey by using dual microdialysis sampling and capillary hydrophilic interaction chromatography–mass spectrometry

“…Such marker, that hint upon the adequacy of energy and metabolite supply are of great importance for the detection of onset of neurodegenerative diseases [41]. In the human brain, a lactate/pyruvate ratio above 40 indicates an "energy crisis" [42]. Additionally it was shown that lactate can increase the cerebral blood flow which correlates with an increase of the lactate/pyruvate ratio in the plasma [36].…”