MRL/lpr mice have alterations in brain metabolism as shown with [1H-13C] NMR spectroscopy.
Cerebral glucose metabolism and cerebral blood flow are altered in patients with lupus who have neuropsychiatric manifestations. However, the dynamics of changes in glucose metabolism remain unclear. The present study was undertaken using 1H and 13C nuclear magnetic resonance (NMR) spectroscopy to determine the rates of incorporation of glucose into amino acids and lactate via cell-specific pathways in mice with lupus. In the well-established MRL/lpr lupus mouse model, 24-week-old mice had a significant increase of 30-80% (P<0.001) in total brain glutamine, glutamate and lactate concentrations, while alanine, aspartate, N-acetyl aspartate (NAA) and gamma-aminobutyric acid (GABA) remained unchanged as compared to the congenic MRL+/+control mice. Although succinate concentration was increased in lupus brain, it did not reach statistical significance. Furthermore, 13C isotopomer analysis showed a selective increase of de novo synthesis of lactate from [1-(13)C] glucose through glycolysis resulting in 1.5-fold increased fractional 13C enrichments in lactate in MRL/lpr mice. [4-(13)C] Glutamate, which is synthesized mainly by the neuronal pyruvate dehydogenase, was selectively increased, while [2-(13)C] and [3-(13)C] GABA synthesis were decreased by 25% compared to controls. In accordance with the total concentrations, aspartate synthesis remained unaltered in brains of lupus mice, while alanine synthesis was elevated, indicating increased utilization of alanine. Creatine was unchanged in MRL/lpr mice as compared to controls. An interesting finding was a significant increase (158%, P<0.005) in choline concentration in MRL/lpr mice while the myo-inositol concentration remained the same in both groups. Furthermore a significant increase in total brain water content was observed, indicative of possible edema. In conclusion, the cumulative effect of increased brain lactate synthesis, altered glucose metabolism and intracellular glutamine accumulation could be an important mechanism causing brain pathology in SLE. The alteration in metabolites could alter downstream pathways and cause neurological dysfunction. Future NMR spectroscopic studies using stable isotopes and real-time measurements of metabolic rates, along with levels of metabolites in plasma and cerebrospinal fluid, could be valuable in the elucidation of the cerebral metabolic consequences of systemic lupus erythematosis (SLE) in humans.
Alexander
Jessy J
JJ
Department of Medicine, University of Chicago, 5841 South Maryland Avenue, MC5100 Chicago, IL 60637, USA. jalexand@medicine.bsd.uchicago.edu
Zwingmann
Claudia
C
Quigg
Richard
R
D000409:Alanine / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D001928:Brain Diseases, Metabolic / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D001929:Brain Edema / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D002250:Carbon Radioisotopes; D002794:Choline / Q000378:metabolism; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000096:biosynthesis; D005973:Glutamine / Q000096:biosynthesis; D006019:Glycolysis / Q000502:physiology; D019344:Lactic Acid / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000150:complications*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008822:Mice, Transgenic; D011522:Protons; D015854:Up-Regulation / Q000502:physiology
D000596:Amino Acids; D002250:Carbon Radioisotopes; D011522:Protons; D005973:Glutamine; D019344:Lactic Acid; D018698:Glutamic Acid; D005947:Glucose; D002794:Choline; D000409:Alanine