Soman-induced convulsions: The neuropathology revisited

Baille, Valérie; Clarke, Peter G. H.; Brochier, Guy; Dorandeu, Frédéric; Verna, Jean-Marc; Four, Elise; Lallement, G.; Carpentier, Pierre

doi:10.1016/j.tox.2005.05.028

Cited by 104 publications

(80 citation statements)

References 74 publications

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“…Microglia are also rapidly activated by prolonged seizures (status epilepticus) (Du et al, 1993;Zimmer et al, 1997;Rizzi et al, 2003;Baille et al, 2005). In the present study, we observed evidence of microglial activation as assessed by increased Iba1 immunoreactivity in mice that survived for 24 h after a dose of TETS that often caused lethality and at 2 days after nonlethal doses.…”

supporting

confidence: 62%

“…Certain seizure types including electroconvulsive (Steward, 1994) and kindled seizures (Steward et al, 1992) as well as nerve agent-induced seizures (Baille-Le Crom et al, 1995;Zimmer et al, 1997;Baille et al, 2005) and kainic acid-induced status epilepticus (Rizzi et al, 2003;Ravizza et al, 2005) are associated with the conversion of astrocytes to a reactive state that can be monitored by GFAP expression. There is often a rapid increase in GFAP that may be present at 4 h and persist for up to 4 days (Steward, 1994;Zimmer et al, 1997); with prolonged seizures, the changes can persist for 7 days or more (Baille et al, 2005). Even the seizures associated with sublethal doses of TETS evoked marked increases in GFAP immunoreactivity in cortex and hippocampus 2 and 3 days after exposure.…”

mentioning

confidence: 99%

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Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Żółkowska

Banks

Dhir

et al. 2012

J Pharmacol Exp Ther

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Tetramethylenedisulfotetramine (tetramine; TETS) is a potent convulsant poison that is considered to be a chemical threat agent. To provide a basis for the investigation of antidotes for TETS-induced seizures, we characterized the convulsant activity of TETS in mice and rats when administered by the intraperitoneal, intravenous, oral, and intraventricular routes as a single acute dose and with repeated sublethal doses. In mice, parenteral and oral TETS caused immobility, myoclonic body jerks, clonic seizures of the forelimbs and/or hindlimbs, tonic seizures, and death. The CD 50 values for clonic and tonic seizures after oral administration were 0.11 and 0.22 mg/kg, respectively. Intraventricular administration of TETS (5-100 g) in rats also caused clonic-tonic seizures and death. In mice, repeated sublethal doses of TETS at intervals of 2, 24, and 48 h failed to result in the development of persistent enhanced seizure responsivity ("kindling") as was observed with repeated pentylenetetrazol treatment. In mice, sublethal doses of TETS that produced clonic seizures did not cause observable structural brain damage as assessed with routine histology and Fluoro-Jade B staining 7 days after treatment. However, 1 to 3 days after a single convulsant dose of TETS the expression of glial fibrillary acidic protein, an astrocyte marker, and ionized calcium binding adaptor molecule 1, a microglia marker, were markedly increased in cortex and hippocampus. Although TETS doses that are compatible with survival are not associated with overt evidence of cellular injury or neurodegeneration, there is transient reactive astrocytosis and microglial activation, indicating that brain inflammatory responses are provoked.

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supporting

confidence: 62%

mentioning

confidence: 99%

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Żółkowska

Banks

Dhir

et al. 2012

J Pharmacol Exp Ther

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“…The suggestion is also supported by the fact that higher in vivo activation of p38 was described in a number of animal models of neuronal death and in a variety of DNA damage and/or cell depletion linked with neurodegenerative diseases in humans, including Alzheimer's disease, Pick disease, progressive supranuclear palsy, corticobasal degeneration, Gerstmann-Straussler-Scheinker disease-Indiana kindred, Huntington's disease and frontotemporal dementia with parkinsonism linked to chromosome 17 (Atzori et al, 2001;Ferrer et al, 2001;Hüll et al, 2002;Ferrer et al, 2003). In addition, Baille and his co-workers described during their neurohistopathological observation of soman-poisoned mice increased apoptosis 24 h after soman poisoning, whereas 7 days after soman challenge, a remarkable decrease of cellular density in the CA3 hippocampal field, amygdala as well as endopiriform/piriform cortices was noted (Baille et al, 2005). In these structures, axonal degeneration and extensive reactive gliosis were also observed 7 days after soman intoxication.…”

Section: Discussionmentioning

confidence: 99%

Activation of mitogen activated protein kinase (MAPK) pathways after soman poisoning in rat cerebellar granule neurons

Pejchal

Österreicher

Kassa³

et al. 2008

J of Applied Toxicology

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The expression of activated p38 mitogen-activated protein kinase (MAPK) and activated MAPK transcription factors c-jun, c-myc and elk-1 were examined in rat cerebellum after soman poisoning to determine the pathogenetic mechanism of the non-specific long-term effects of nerve agents. Male Wistar rats were poisoned by intramuscular administration of soman at a dose 60 microg kg(-1) (70% LD(50)) and samples were taken 1, 7 and 14 days after poisoning, immunohistochemically stained and p-p38MAPK, p-c-jun, p-c-myc and p-elk-1 expressions were measured using image analysis. Control groups were administered with saline instead of soman. The expression of activated p38MAPK and c-myc increased 14 days after soman poisoning while c-jun and elk-1 expressions remained unchanged 1, 7 and 14 days after soman poisoning. Delayed activation of p38 MAPK and its targets might be involved in the pathogenetic mechanism of the long-term neurophysiological toxic effects of nerve agents.

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“…The activation of potentially harmful inflammation through specific MAPK pathways in the seizing animals is likely an initial event that, if unabated, triggers apoptosis and sustains persistent seizures (Abraham and Clark, 2006;Baille et al, 2005;Herlaar and Brown, 1999;McLeod et al, 1983;Zhang and Liu, 2002). On the other hand, in the non-seizing animal, mechanisms that are able to control or inhibit the inflammatory response would constitute innate neuroprotective mechanisms.…”

Section: Differential Activation Of Mapk Sub-pathways Distinguished Tmentioning

confidence: 99%

Neuroprotective mechanisms activated in non-seizing rats exposed to sarin

Spradling-Reeves

Dillman

et al. 2015

Brain Research

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Exposure to organophosphate (OP) nerve agents, such as sarin, may lead to uncontrolled seizures and irreversible brain injury and neuropathology. In rat studies, a median lethal dose of sarin leads to approximately half of the animals developing seizures. Whereas previous studies analyzed transcriptomic effects associated with seizing sarin-exposed rats, our study focused on the cohort of sarin-exposed rats that did not develop seizures. We analyzed the genomic changes occurring in sarin-exposed, non-seizing rats and compared differentially expressed genes and pathway activation to those of seizing rats. At the earliest time point (0.25 h) and in multiple sarin-sensitive brain regions, defense response genes were commonly expressed in both groups of animals as compared to the control groups. All sarin-exposed animals activated the MAPK signaling pathway, but only the seizing rats activated the apoptotic-associated JNK and p38 MAPK signaling sub-pathway. A unique phenotype of the non-seizing rats was the altered expression levels of genes that generally suppress inflammation or apoptosis. Importantly, the early transcriptional response for inflammation- and apoptosis-related genes in the thalamus showed opposite trends, with significantly down-regulated genes being up-regulated, and vice versa, between the seizing and non-seizing rats. These observations lend support to the hypothesis that regulation of anti-inflammatory genes might be part of an active and sufficient response in the non-seizing group to protect against the onset of seizures. As such, stimulating or activating these responses via pretreatment strategies could boost resilience against nerve agent exposures.

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Soman-induced convulsions: The neuropathology revisited

Cited by 104 publications

References 74 publications

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Characterization of Seizures Induced by Acute and Repeated Exposure to Tetramethylenedisulfotetramine

Activation of mitogen activated protein kinase (MAPK) pathways after soman poisoning in rat cerebellar granule neurons

Neuroprotective mechanisms activated in non-seizing rats exposed to sarin

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