title: Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice.
abstract: Epileptic seizures and status epilepticus (SE) induced by the poisoning with organophosphorus nerve agents (OP), like soman, are accompanied by neuroinflammation whose role in seizure-related brain damage (SRBD) is not clear. Antagonists of the NMDA glutamate ionotropic receptors are currently among the few compounds able to arrest seizures and provide neuroprotection even during refractory status epilepticus (RSE). Racemic ketamine (KET), in combination with atropine sulfate (AS), was previously shown to counteract seizures and SRBD in soman-poisoned guinea-pigs. In a mouse model of severe soman-induced SE, we assessed the potentials of KET/AS combinations as a treatment for SE/RSE-induced SRBD and neuroinflammation. When starting 30min after soman challenge, a protocol involving six injections of a sub-anesthetic dose of KET (25mg/kg) was evaluated on body weight loss, brain damage, and neuroinflammation whereas during RSE, anesthetic protocols were considered (KET 100mg/kg). After confirming that during RSE, KET injection was to be repeated despite some iatrogenic deaths, we used these proof-of-concept protocols to study the changes in mRNA and related protein contents of some inflammatory cytokines, chemokines and adhesion molecules in cortex and hippocampus 48h post-challenge. In both cases, the KET/AS combinations showed important neuroprotective effects, suppressed neutrophil granulocyte infiltration and partially suppressed glial activation. KET/AS could also reduce the increase in mRNA and related pro-inflammatory proteins provoked by the poisoning. In conclusion, the present study confirms that KET/AS treatment has a strong potential for SE/RSE management following OP poisoning. The mechanisms involved in the reduction of central neuroinflammation remain to be studied.
authors.affiliation: Département de Toxicologie et risques chimiques, Institut de Recherche Biomédicale des armées - Centre de recherches du Service de santé des armées IRBA-CRSSA, La Tronche cedex, France. franck.dhote@irba.fr
authors.forename: Franck
authors.initials: F
authors.lastname: Dhote
authors.forename: Pierre
authors.initials: P
authors.lastname: Carpentier
authors.forename: Laure
authors.initials: L
authors.lastname: Barbier
authors.forename: André
authors.initials: A
authors.lastname: Peinnequin
authors.forename: Valérie
authors.initials: V
authors.lastname: Baille
authors.forename: Fabien
authors.initials: F
authors.lastname: Pernot
authors.forename: Guy
authors.initials: G
authors.lastname: Testylier
authors.forename: Claire
authors.initials: C
authors.lastname: Beaup
authors.forename: Annie
authors.initials: A
authors.lastname: Foquin
authors.forename: Fréderic
authors.initials: F
authors.lastname: Dorandeu
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001285:Atropine / Q000494:pharmacology*; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002619:Chemical Warfare Agents / Q000633:toxicity*; D018946:Chemokine CCL5 / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000235:genetics / Q000276:immunology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009457:Neuroglia / Q000276:immunology; D009504:Neutrophils / Q000276:immunology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D011897:Random Allocation; D012999:Soman / Q000633:toxicity*; D013226:Status Epilepticus / Q000139:chemically induced* / Q000188:drug therapy* / Q000276:immunology
chemical_list: D002619:Chemical Warfare Agents; D018946:Chemokine CCL5; D054360:Chemokine CXCL1; D018691:Excitatory Amino Acid Antagonists; D018727:Muscarinic Antagonists; D012333:RNA, Messenger; D007649:Ketamine; D001285:Atropine; D012999:Soman