Hyperosmolar treatment of soman-induced brain lesions in mice: evaluation of the effects through diffusion-weighted magnetic resonance imaging and through histology.

International audiencePURPOSE: A convulsive dose of soman induces seizure-related brain damage (SRBD), including cerebral edema (CE) and neuronal loss. In the present study on soman-intoxicated mice, we applied diffusion-weighted magnetic resonance imaging (DW-MRI) and quantitative histology, and we measured brain water content to investigate the antiedematous and neuroprotective efficacies of two hyperosmolar treatments: mannitol (Mann) and hypertonic saline (HTS). METHODS: Mice intoxicated with soman (172 microg/kg after a protective pretreatment) were administered 1 min and 5-h post-challenge an i.v. bolus of saline, of Mann or of HTS. 1 day later, mice were examined with DW-MRI and then sacrificed for brain histology. Additional animals were intoxicated and treated similarly for the measurement of the brain water content (dry/wet weight method). RESULTS: In intoxicated controls, a significant decrease of the apparent diffusion coefficient (ADC), numerous damaged (eosinophilic) cells, high edema scores, and a significant increase in brain water content were detected 24-h post-challenge in sensitive brain structures. These soman-induced changes were not significantly modified by treatment with Mann or HTS. CONCLUSIONS: Treatment with hyperosmolar solutions did not reduce the effects of soman on ADC, on cell damage and on CE. Therefore, despite similar treatment protocols, the prominent protection by Mann that was previously demonstrated by others in poisoned rats, was not reproduced in our murine model

Prediction of soman-induced cerebral damage by distortion product otoacoustic emissions.

International audienceThe organophosphorus nerve agent soman is an irreversible cholinesterase (ChE) inhibitor that can produce long-lasting seizures and seizure-related brain damage (SRBD) in which acetylcholine and glutamate are involved. Since these neurotransmitters play a key-role in the auditory function, it was hypothesized that a hearing test may be an efficient way for detecting the central effects of soman intoxication. In the present study, distortion product otoacoustic emissions (DPOAEs), a non-invasive audiometric method, were used in rats administered with soman (70 μg/kg). Four hours post-soman, DPOAE intensities were significantly decreased. They returned to baseline one day later. The amplitude of the temporary drop of the DPOAEs was well related to the severity of the intoxication. The greatest change was recorded in the rats that survived long-lasting convulsions, i.e. those that showed the highest ChE inhibition in brain and severe encephalopathy. Furthermore, the administration, immediately after soman, of a three-drug therapy composed of atropine sulfate, HI-6 and avizafone abolished the convulsions, the transient drop of DPOAEs at 4h and the occurrence of SRBD at 28 h without modifying brain ChE inhibition. This showed that DPOAE change was not directly related to soman-induced inhibition of cerebral ChE but rather to its neuropathological consequences. The present findings strongly suggest that DPOAEs represent a promising non-invasive tool to predict SRBD occurrence in nerve agent poisoning and to control the efficacy of a neuroprotective treatment

Prolonged inflammatory gene response following soman-induced seizures in mice.

International audienceFollowing exposure to the organophosphorus nerve agent soman, the development of long-lasting seizures and build-up of irreversible seizure-related brain damage (SRBD) still represent a therapeutic challenge. A neuro-inflammatory reaction takes place in the brain after poisoning but its characteristics and potential role in SRBD and post-status epilepticus epileptogenesis is not well understood. In the present study we have analyzed by quantitative RT-PCR the time course of changes in mRNA levels of IL-1beta, TNFalpha, IL-6, ICAM-1 and SOCS3 in hippocampus, whole cortex and cerebellum in a mouse model of severe seizures and neuropathy up to 7 days after poisoning. Mice received an injection of the oxime HI-6 (50mg/kg) 5 min prior to the administration of a convulsive dose of soman (172 microg/kg). An important and highly significant increase of the five mRNA levels was recorded in cortex and hippocampus. In the cortex, the activation was generally detected as early as 1h post-intoxication with a peak response recorded between 6 and 24h. In the hippocampus, the gene up-regulation was delayed to 6h post-soman and the peak response observed between 24 and 48 h. After peaking, the response declined (except for ICAM in the hippocampus) but remained elevated, some of them significantly, at day 7. Interestingly, in the cerebellum, some changes were also observed but were several fold smaller. In conclusion, the present study indicates a quick neuro-inflammatory gene response that does not subside over 7 days suggesting a potential role in the neurological consequences of soman-induced status epilepticus

Cerebral edema induced in mice by a convulsive dose of soman. Evaluation through diffusion-weighted magnetic resonance imaging and histology.

International audiencePURPOSE: In the present study, diffusion-weighted magnetic resonance imaging (DW-MRI) and histology were used to assess cerebral edema and lesions in mice intoxicated by a convulsive dose of soman, an organophosphate compound acting as an irreversible cholinesterase inhibitor. METHODS: Three hours and 24 h after the intoxication with soman (172 microg/kg), the mice were anesthetized with an isoflurane/N(2)O mixture and their brain examined with DW-MRI. After the imaging sessions, the mice were sacrificed for histological analysis of their brain. RESULTS: A decrease in the apparent diffusion coefficient (ADC) was detected as soon as 3 h after the intoxication and was found strongly enhanced at 24 h. A correlation was obtained between the ADC change and the severity of the overall brain damage (edema and cellular degeneration): the more severe the damage, the stronger the ADC drop. Anesthesia was shown to interrupt soman-induced seizures and to attenuate edema and cell change in certain sensitive brain areas. Finally, brain water content was assessed using the traditional dry/wet weight method. A significant increase of brain water was observed following the intoxication. CONCLUSIONS: The ADC decrease observed in the present study suggests that brain edema in soman poisoning is mainly intracellular and cytotoxic. Since entry of water into the brain was also evidenced, this type of edema is certainly mixed with others (vasogenic, hydrostatic, osmotic). The present study confirms the potential of DW-MRI as a non-invasive tool for monitoring the acute neuropathological consequences (edema and neurodegeneration) of soman-induced seizures