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Cerebral glutamine and glutamate levels in relation to compromised energy metabolism: a microdialysis study in subarachnoid hemorrhage patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
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2007 (English)In: Journal of Cerebral Blood Flow and Metabolism, ISSN 0271-678X, E-ISSN 1559-7016, Vol. 27, no 7, 1309-1317 p.Article in journal (Refereed) Published
Abstract [en]

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=-0.66), 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.

Place, publisher, year, edition, pages
2007. Vol. 27, no 7, 1309-1317 p.
Keyword [en]
brain, glutamate, glutamine, lactate, microdialysis, pyruvate
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-97026DOI: 10.1038/sj.jcbfm.9600433ISI: 000247375000002PubMedID: 17228333OAI: oai:DiVA.org:uu-97026DiVA: diva2:171794
Available from: 2008-04-10 Created: 2008-04-10 Last updated: 2016-05-02
In thesis
1. Glutamate Turnover and Energy Metabolism in Brain Injury: Clinical and Experimental Studies
Open this publication in new window or tab >>Glutamate Turnover and Energy Metabolism in Brain Injury: Clinical and Experimental Studies
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

During brain activity neurons release the major excitatory transmitter glutamate, which is taken up by astrocytes and converted to glutamine. Glutamine returns to neurons for re-conversion to glutamate. This glutamate-glutamine cycle is energy demanding. Glutamate turnover in injured brain was studied using an animal iron-induced posttraumatic epilepsy model and using neurointensive care data from 33 patients with spontaneous subarachnoid hemorrhage (SAH). Immunoblotting revealed that the functional form of the major astrocytic glutamate uptake protein GLT-1 was decreased 1-5 days following a cortical epileptogenic iron-injection, presumably due to oxidation-induced aggregation. Using microdialysis it was shown that the GLT-1 decrease was associated with increased interstitial glutamate levels and decreased interstitial glutamine levels. The results indicate a possible posttraumatic and post-stroke epileptogenic mechanism. Analysing 3600 microdialysis hours from patients it was found that the interstitial lactate/pyruvate (L/P) ratio correlate with the glutamine/glutamate ratio (r =-0.66). This correlation was as strong as the correlation between L/P and glutamate (r=0.68) and between lactate and glutamate (r=0.65). Pyruvate and glutamine correlated linearly (r=0.52). Energy failure periods, defined as L/P>40, were associated with high interstitial glutamate levels. Glutamine increased or decreased during energy failure periods depending on pyruvate. Energy failure periods were clinically associated with delayed ischemic neurological deficits (DIND) or development of radiologically verified infarcts, confirming that L/P>40 is a pathological microdialysis pattern that can predict ischemic deterioration after SAH. DIND-associated microdialysis patterns were L/P elevations and surges in interstitial glutamine. Glutamine and pyruvate correlated with the cerebral perfusion pressure (r=0.25, r=0.24). Glutamine and the glutamine/glutamate ratio correlated with the intracranial pressure (r=-0.29, r=0.40). Glutamine surges appeared upon substantial lowering of the intracranial pressure by increased cerebrospinal fluid drainage. Increased interstitial glutamine and pyruvate levels may reflect augmented astrocytic glycolysis in recovering brain tissue with increased energy demand due to a high glutamate-glutamine turnover.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 71 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 329
Keyword
Neurosciences, glutamate, glutamine, lactate, pyruvate, microdialysis, GLT-1, energy metabolism, intracranial pressure, cerebral perfusion pressure, subarachnoid hemorrhage, ischemia, epilepsy, Neurovetenskap
Identifiers
urn:nbn:se:uu:diva-8630 (URN)978-91-554-7155-2 (ISBN)
Public defence
2008-05-02, Rudbecksalen, Rudbecklaboratoriet, Glunten-området, Uppsala Science Park, Dag Hammarskjölds väg 20, Uppsala, 09:15
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Available from: 2008-04-10 Created: 2008-04-10Bibliographically approved

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Samuelsson, CarolinaHillered, LarsZetterling, MariaEnblad, PerHesselager, GöranRyttlefors, MatsMarklund, NiklasNilsson, Pelle

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