Assessing Susceptibility to Epilepsy in Three Rat Strains Using Brain Metabolic Profiling Based on HRMAS NMR Spectroscopy and Chemometrics

Abstract

The possibility that a metabolomic approach can inform about the pathophysiology of a given form of epilepsy was addressed. Using chemometric analyses of HRMAS NMR data, we compared several brain structures in three rat strains with different susceptibilities to absence epilepsy: Genetic Absence Epilepsy Rats from Strasbourg (GAERS), Non Epileptic Control rats (NEC), and Wistar rats. Two ages were investigated: 14 days postnatal (P14) before the onset of seizures and 5 month old adults with fully developed seizures (Adults). The relative concentrations of 19 metabolites were assessed using (1)H HRMAS NMR experiments. Univariate and multivariate analyses including multiblock models were used to identify the most discriminant metabolites. A strain-dependent evolution of glutamate, glutamine, scyllo-inositol, alanine, and glutathione was highlighted during cerebral maturation. In Adults, data from somatosensory and motor cortices allowed discrimination between GAERS and NEC rats with higher levels of scyllo-inositol, taurine, and phosphoethanolamine in NEC. This epileptic metabolic phenotype was in accordance with current pathophysiological hypothesis of absence epilepsy (i.e., seizure-generating and control networks) and putative resistance of NEC rats and was observed before seizure onset. This methodology could be very efficient in a clinical context.

Brain Metabolic Changes in Rats following Acoustic Trauma

“…Over the last decade, metabolomics has become one of the major “omics” tools in understanding disease pathology, identifying biomarkers, improving diagnosis and developing personalized therapy (see Botas et al, 2015; Shah et al, 2015 for reviews). In addition, brain metabolomics has been used to understand the pathology and identify potential markers for neurodegenerative diseases in both animal models and human post-mortem tissues due to the fact that metabolic changes in the brain are more likely to reflect disease etiology than those in peripheral biofluids (Pears et al, 2005; Salek et al, 2010; Graham et al, 2013; Fauvelle et al, 2015; Xu et al, 2016). In the present study, 107 small molecules were detected from 12 different brain regions and 88 of them were authentically identified.…”

Developmental changes of GABA immunoreactivity in cortico-thalamic networks of an absence seizure model

“…It is possible that alongside the “exclusion” of genes predisposing to the AS phenotype, other genes have been selected in NEC rats that are not directly responsible for the lack of ASs in this strain ( Powell et al., 2014 ). Indeed, NEC rats weigh less ( Fauvelle et al., 2015 , Marques-Carneiro et al., 2014 , Powell et al., 2014 ), have a smaller whole brain volume, a larger amygdala, a reduced night-time locomotor activity, a stronger anxiety-like behaviour in the open field and elevated plus-maze ( Marques-Carneiro et al., 2014 ), and a different metabolic profile ( Fauvelle et al., 2015 ) than Wistar rats. Therefore, these data suggest that NEC rats may not be an appropriate or sufficient control strain for GAERS and indicates that normal Wistar rats should also be used in comparative studies.…”

In vivo γ‐aminobutyric acid increase as a biomarker of the epileptogenic zone: An unbiased metabolomics approach

“…Among analytical methods, high‐resolution magic angle spinning (HRMAS) nuclear magnetic resonance spectroscopy (MRS) avoids chemical extraction and sample destruction, a great advantage for clinical follow‐up and traceability 6 . Using this approach, we previously described the specific metabolic profile of the seizure initiation area in a genetic model of epilepsy 7 . Metabolomics could therefore improve EZ localization, a key issue in particular for MRI‐negative patients.…”