title: Prediction of neuroprotective treatment efficiency using a HRMAS NMR-based statistical model of refractory status epilepticus on mouse: a metabolomic approach supported by histology.
abstract: This work presents a model combining quantitative proton HRMAS NMR data and PLS-DA for neuropathology and neuroprotection evaluation. Metabolic data were also confronted to histopathological results obtained using the same experimental conditions. Soman, when not lethal, can induce status epilepticus (SE), brain damage, histological lesions, and profound cerebral metabolic disorders as revealed using (1)H HRMAS NMR. Our challenge was to evaluate delayed treatments, which could control refractory SE and avoid brain lesions. For this aim, we have built a statistical model of soman intoxication describing brain metabolite evolution during 7 days. We have then used this model to evaluate the efficiency of a combination of ketamine/atropine (KET/AS) administrated 1 and 2 h after SE induction, compared to the immediate anticonvulsant therapy midazolam/atropine sulfate (MDZ/AS). Furthermore, quantitation of HRMAS NMR data allowed us to follow individual evolution of 17 metabolites. N-Acetylaspartate, lactate, or taurine presented a long lasting disruption, while glutamine, alanine, glycerophosphocholine and myo-inositol showed disruptions for 3 days with a reversion at day 7. These changes were completely normalized by the administration of MDZ/AS. Interestingly, they were also almost completely reversed by KET/AS 1 h postsoman. This work suggests further the predictive interest of HRMAS and PLS-DA for neuropathology/neuroprotection studies and also confirms, on the metabolic aspects, the neuroprotective potentials of KET/AS combinations for the delayed treatment of soman-induced SE.
authors.affiliation: Département Effets Biologiques des Rayonnements, IRBA-CRSSA, La Tronche, France. Florence.fauvelle@free.fr
authors.forename: Florence
authors.initials: F
authors.lastname: Fauvelle
authors.forename: Pierre
authors.initials: P
authors.lastname: Carpentier
authors.forename: Frederic
authors.initials: F
authors.lastname: Dorandeu
authors.forename: Annie
authors.initials: A
authors.lastname: Foquin
authors.forename: Guy
authors.initials: G
authors.lastname: Testylier
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001285:Atropine / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004359:Drug Therapy, Combination; D007649:Ketamine / Q000494:pharmacology / Q000627:therapeutic use*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055442:Metabolome; D051379:Mice; D008874:Midazolam / Q000494:pharmacology / Q000627:therapeutic use; D015999:Multivariate Analysis; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D025341:Principal Component Analysis; D012999:Soman; D013226:Status Epilepticus / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D000927:Anticonvulsants; D015415:Biomarkers; D018696:Neuroprotective Agents; D007649:Ketamine; D001285:Atropine; D012999:Soman; D008874:Midazolam