Combinations of ketamine and atropine are neuroprotective and reduce neuroinflammation after a toxic status epilepticus in mice

Journal Article · Thu Mar 01 04:00:00 EST 2012 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2011.12.024· OSTI ID:22215255

Dhote, Franck ^[1]; Carpentier, Pierre; Barbier, Laure ^[1]; Peinnequin, André ^[2]; Baille, Valérie; Pernot, Fabien; Testylier, Guy; Beaup, Claire; Foquin, Annie ^[1]; others, and

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1. Département de Toxicologie et risques chimiques, Institut de Recherche Biomédicale des armées – Centre de recherches du Service de santé des armées IRBA-CRSSA, 24 avenue des Maquis du Grésivaudan, B.P. 87, 38702 La Tronche cedex (France)
2. Département Effets biologiques des rayonnements, Institut de Recherche Biomédicale des armées – Centre de recherches du Service de santé des armées IRBA-CRSSA, 24 avenue des Maquis du Grésivaudan, B.P. 87, 38702 La Tronche cedex (France)

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 30 min after soman challenge, a protocol involving six injections of a sub-anesthetic dose of KET (25 mg/kg) was evaluated on body weight loss, brain damage, and neuroinflammation whereas during RSE, anesthetic protocols were considered (KET 100 mg/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 48 h 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. -- Highlights: ► During soman-induced status epilepticus, ketamine-atropine limit brain damage. ► Molecular neuroinflammatory response is strongly decreased. ► Glial activation is not fully suppressed.

• OSTI ID: 22215255
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 259; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
ANESTHETICS
ATROPINE
GUINEA PIGS
HIPPOCAMPUS
INFLAMMATION
LYMPHOKINES
MAGNESIUM 25
MESSENGER-RNA
MICE
NEUTROPHILS
RECEPTORS