Hypertonic mannitol in mice poisoned by a convulsive dose of soman: antilethal activity without neuroprotection.
A convulsive dose of soman induces seizure-related brain damage (SRBD), including cerebral edema (CE) and cell death. In 1993, an American study demonstrated that hypertonic mannitol (Mann) intravenously (i.v.) administered 1 min and 5h post-soman was an effective neuroprotectant in intoxicated rats. Using a similar protocol, we recently failed to reproduce this success in intoxicated mice. In the present study, also performed in mice, the persistence or the amplitude of the osmotic load was increased by reducing the time interval between two injections of Mann or by augmenting the number of injections. Mice were pre-treated with the oxime HI-6 and then intoxicated with a convulsive dose of soman (172 microg/kg). Afterward, they were administered a first i.v. bolus of Mann 20% 1 min post-challenge and a second one either 5, or 2, or 1h after. Additional animals were given either one (1 min post-soman), or two (1 min and 1h post-soman), or three (1 min, 1 and 2h post-soman) series of three injections of Mann at 5 min intervals. Non-intoxicated mice treated with Mann (same protocols as above) and intoxicated mice treated with Mann vehicle (saline) served as controls. At 24h post-intoxication, the survivors were sacrificed and their brains prepared for quantitative histological assessment of cell damage, CE, and ventricle size. Whatever the protocol, Mann had no effect on soman-induced convulsions but did provide considerable antilethal activity. Histologically, Mann did not reduce the cell damage or CE. It even showed a dose-dependent trend toward aggravation of SRBD in some regions and promoted subarachnoid hemorrhages. Conversely, in one of the treatment protocol, it reduced soman-induced enlargement of ventricle size. Although treatment with hypertonic Mann showed some benefit on mortality and ventricle size, it failed to be an effective neuroprotector in soman-intoxicated mice and even increased the detrimental impact of soman at the cerebral level. Therefore, no clear recommendation could be drawn from the present study in view of a possible clinical use of hyperosmolar treatment in the medical management of soman poisoning.
Carpentier
Pierre
P
Institut de Recherche Biomédicale des Armées, Centre de Recherches du Service de Santé des Armées, Département de Toxicologie, BP87, F-38702 La Tronche Cedex, France. pierrecarpentier@crssa.net
Foquin
Annie
A
Dorandeu
Frédéric
F
D000818:Animals; D003292:Convulsants / Q000506:poisoning*; D008297:Male; D008353:Mannitol / Q000627:therapeutic use*; D051379:Mice; D009994:Osmolar Concentration; D011041:Poisoning / Q000188:drug therapy; D012640:Seizures / Q000139:chemically induced*; D012999:Soman / Q000506:poisoning*
D003292:Convulsants; D008353:Mannitol; D012999:Soman