期刊
MOLECULAR BIOSYSTEMS
卷 11, 期 5, 页码 1462-1471出版社
ROYAL SOC CHEMISTRY
DOI: 10.1039/c5mb00049a
关键词
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资金
- Dutch Organization for Scientific Research
- EU Marie Curie IAPP Program BRAINPATH [612360]
- EU EUROHEADPAIN [602633]
- LUMC Fellowship
- Marie Curie Career Integration Grant [294233]
- Center of Medical System Biology (CMSB)
- Swiss National Scientific Foundation [P2GEP3_155633]
- Swiss National Science Foundation (SNF) [P2GEP3_155633] Funding Source: Swiss National Science Foundation (SNF)
Migraine is a common brain disorder characterized by recurrent attacks of severe headaches and other neurological symptoms. In one-third of patients headaches are accompanied by auras, which consist of transient visual and sensory disturbances, believed to be caused by cortical spreading depression (CSD). CSD is characterized by a wave of neuronal and glial depolarization with concomitant changes in metabolite concentrations in the brain and cerebrospinal fluid. It remains unknown whether CSD-induced brain metabolic changes can be captured outside the central nervous system, i.e., in peripheral fluids. This study investigated plasma metabolic changes in transgenic mice that harbor a gene mutation in voltage-gated Ca(V)2.1 Ca2+ channels previously identified in patients with familial hemiplegic migraine, a subtype of migraine with auras. The use of a mouse model allows investigation of molecular changes occurring shortly after CSD, which is notoriously difficult in patients. Capillary electrophoresis - mass spectrometry was used for the analysis of plasma samples to obtain, for the first time, a comprehensive view of molecular changes immediately after experimentally induced CSD. Multivariate data analysis showed a clear distinction between profiles of transgenic and wild-type animals after CSD. Two metabolites considered important for this discrimination were tentatively identified as being lysine and its by-product pipecolic acid with additional evidence provided by hydrophilic interaction chromatography combined with tandem mass spectrometry. The changed metabolites suggest a compensatory increase in GABAergic neurotransmission upon enhanced excitatory neurotransmission. These results show that CSD induces metabolic remodeling in transgenic migraine mice that can be captured and measured in plasma.
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