Analysis of brain metabolites by gas chromatography–mass spectrometry reveals the risk–benefit concerns of prednisone in MRL/lpr lupus mice
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a common cause of disability in systemic lupus erythematosus (SLE). This study aims to investigate the metabolic changes in the hypothalamus and frontal cortex in lupus-prone MRL/lpr mice.
Metabolic changes were analyzed using gas chromatography-mass spectrometry (GC–MS).
According to the principal component analysis (PCA), the metabolic profiles were different between the frontal cortex and hypothalamus, but they were comparable between MRL/lpr and MRL/MpJ mice (16 weeks of age). By OPLS-DA, eight cortical and six hypothalamic differential metabolites were identified in MRL/lpr as compared to MRL/MpJ mice. Among these differential metabolites, we found a decrease of N-acetyl-l-aspartate (NAA, a potential marker of neuronal integrity), an increase of pyruvate and a decrease of glutamate in the frontal cortex but not in the hypothalamus. Prednisone treatment (3 mg/kg from 8 weeks of age) relieved the decrease of NAA but further increased the accumulation of pyruvate in the frontal cortex, additionally affected eight enriched pathways in the hypothalamus, and led to significant imbalances between the excitation and inhibition in both the frontal cortex and hypothalamus.
These results suggest that the frontal cortex may be more preferentially affected than the hypothalamus in SLE. Prednisone disrupted rather than relieved metabolic abnormalities in the brain, especially in the hypothalamus, indicating that the risk–benefit balance of prednisone for SLE or NPSLE remains to be further evaluated.
KeywordsBrain Lupus Glucocorticoids Metabolomics Gas chromatography-mass spectrometry
Analysis of variance
Glucocorticoids (prednisone group)
Gas chromatography-mass spectrometry
MRL/lpr mice (control)
MRL/MpJ mice (normal group)
Orthogonal partial least square-discriminant analysis
Principal component analysis
Systemic lupus erythematosus
Variable importance in projection
Z.X. would like to thank all members of Filiano Lab, Kurtzberg Lab and Marcus Center for Cellular Cures (MC3) at Duke University.
ZX, JZ and CP designed the study. FL, SL, MX and HL performed the experiments. JZ, FL and ZX analyzed the data. SW and ZX were involved with the interpretation of data in the manuscript. ZX wrote the manuscript in consultation with JZ and FL.
This work was funded by the Program of Zhejiang TCM Science and Technology Plan (2018ZZ007 and 2017ZA064), the National Natural Science Foundation of China (81673623 and 81873102), and partly the Foundation of the Zhejiang Chinese Medical University (ZYX2018002 and 2018ZG24), Special Scientific Project of Traditional Chinese Medicine (201507001-4) and National Natural Science Foundation of China (81873266).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no competing interests.
Experiments were approved by the Institutional Animal Care and Use Committee of Zhejiang Chinese Medical University (#ZSLL-2018-30).
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