title: Plasma metabolic profiling after cortical spreading depression in a transgenic mouse model of hemiplegic migraine by capillary electrophoresis--mass spectrometry.
abstract: 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 CaV2.1 Ca(2+) 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.
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Reinald
authors: R
authors: Shyti
authors: Isabelle
authors: I
authors: Kohler
authors: Bart
authors: B
authors: Schoenmaker
authors: Rico J E
authors: RJ
authors: Derks
authors: Michel D
authors: MD
authors: Ferrari
authors: Else A
authors: EA
authors: Tolner
authors: Oleg A
authors: OA
authors: Mayboroda
authors: Arn M J M
authors: AM
authors: van den Maagdenberg
mesh_terms: D000818:Animals; D013181:Cortical Spreading Depression / Q000235:genetics; D004195:Disease Models, Animal; D019075:Electrophoresis, Capillary; D008297:Male; D013058:Mass Spectrometry; D055442:Metabolome; D055432:Metabolomics / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D020325:Migraine with Aura / Q000235:genetics / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism*; D015203:Reproducibility of Results