Histomorphogenesis of Soman-Induced Encephalocardiomyopathy in Sprague-Dawley Rats

Tryphonas, L.; Clement, John G.

doi:10.1177/019262339502300316

Cited by 38 publications

(29 citation statements)

References 60 publications

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“…These clinical signs are accompanied by central nervous system (CNS) and myocardial morphologic lesions (4,5,9,11,12,14,24,27,31,33,36,38,39,54). CNS lesions have been reported in the piriform cortex, amygdala, thalamus, hippocampus, and substantia nigra (4,5,9,11,12,14,27,33,36,38,39,54,57). Myocardial degeneration has been reported to be limited to the left ventricle and to progress to fibrosis (15,36,47,54,56,57).…”

Section: Introductionmentioning

confidence: 99%

Early Histopathologic and Ultrastructural Changes in the Heart of Sprague-Dawley Rats Following Administration of Soman

Tryphonas

Veinot

Clement³

1996

Toxicol Pathol

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Male Sprague-Dawley rats were given atropine methylnitrate (20 mg/kg) and HI-6 (125 mg/kg) ip 10 min before a single injection of 130 micrograms soman/kg sc, and the heart was examined by light and electron microscopy 10, 25, 45, 90, and 180 min after the onset of seizures. Seizures appeared within 6-11 min after treatment. Control rats were given saline sc in place of soman. Early myocardial lesions consisting of hypercontraction and hyperextension of sarcomeres, focal myocytolysis, and contraction bands were detected in individual or groups of myocardial fibers. Hypercontraction was characterized by shortening of the sarcomere length, disappearance of the I and H bands, and thickening of the Z line. In contrast, hyperextended sarcomeres had thickened I and H bands. Myocytolysis was characterized by a progressively severe focal dissolution of myofilaments and edema of the affected sarcoplasmic area. Contraction bands appeared to result from the breakdown of markedly hypercontracted myofibril bundles. Due to the presence of a number of surviving myofilaments and the preservation of the sarcolemmal tube, distortion of the overall myocytic structure was minimal. Changes in the mitochondria and other intracellular organelles were also minimal and nonspecific. The close resemblance of morphologic findings to those induced by catecholamines supports the view that soman-induced myocardial damage is secondary to a treatment-related release of unphysiologic amounts of endogenous catecholamines.

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Section: Introductionmentioning

confidence: 99%

Early Histopathologic and Ultrastructural Changes in the Heart of Sprague-Dawley Rats Following Administration of Soman

Tryphonas

Veinot

Clement³

1996

Toxicol Pathol

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“…During severe acute OP intoxication, initial seizures rapidly progress to status epilepticus and finally result in profound brain damage (Shih and McDonough 1997; Tryphonas and Clement 1995). The proposed sequence of events consists of three phases: an early cholinergic phase, a transitional phase of mixed cholinergic/non-cholinergic modulation, and finally, a non-cholinergic phase (Shih and McDonough 1997).…”

Section: Discussionmentioning

confidence: 99%

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

et al. 2016

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Acute organophosphorus (OP) intoxication is a worldwide clinical and public health problem. In addition to cholinergic crisis, neurodegeneration and brain damage are hallmarks of the severe form of this toxidrome. Recently, we generated a chemical model of severe acute OP intoxication in zebrafish that is characterized by altered head morphology and brain degeneration. The pathophysiological pathways resulting in brain toxicity in this model are similar to those described in humans. The aim of this study was to assess the predictive power of this zebrafish model by testing the effect of a panel of drugs that provide protection in mammalian models. The selected drugs included “standard therapy” drugs (atropine and pralidoxime), reversible acetylcholinesterase inhibitors (huperzine A, galantamine, physostigmine and pyridostigmine), N-methyl-d-aspartate (NMDA) receptor antagonists (MK-801 and memantine), dual-function NMDA receptor and acetylcholine receptor antagonists (caramiphen and benactyzine) and anti-inflammatory drugs (dexamethasone and ibuprofen). The effects of these drugs on zebrafish survival and the prevalence of abnormal head morphology in the larvae exposed to 4 µM chlorpyrifos oxon [1 × median lethal concentration (LC50)] were determined. Moreover, the neuroprotective effects of pralidoxime, memantine, caramiphen and dexamethasone at the gross morphological level were confirmed by histopathological and transcriptional analyses. Our results demonstrated that the zebrafish model for severe acute OP intoxication has a high predictive value and can be used to identify new compounds that provide neuroprotection against severe acute OP intoxication.Electronic supplementary materialThe online version of this article (doi:10.1007/s00204-016-1851-3) contains supplementary material, which is available to authorized users.

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“…It is well established that EGSA, which accompanies exposure to OP agents, contributes to the profound brain damage and cardiac pathology observed after intoxication with OP compounds (Lemercier et al 1983;Shih 1993, 1997;Mcleod 1985;Mcleod et al 1984;Petras 1981;Philippens et al 1981;Singer et al 1987;Tryphonas and Clement 1995;Tryphonas et al 1996). These findings emphasize the importance of identifying possible pharmacological interventions that will minimize the damage induced by the OP intoxication.…”

Section: Discussionmentioning

confidence: 99%

“…This creates a problem of casualty management for exposed subjects, and can progress to status epilepticus (SE) (Glenn et al 1987;Koplovitz and Skvorak 1998;Lipp 1968;Shih 1993, 1997;Shih et al 1991). It has been shown that SE may lead to profound brain damage, as well as cardiac pathology (Tryphonas and Clement 1995;Tryphonas et al 1996).…”

Section: Introductionmentioning

confidence: 99%

Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig

et al. 2002

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Seizures and status epilepticus, which may contribute to brain injury, are common consequences of exposure to organophosphorus (OP) cholinesterase inhibitors. Effective management of these seizures is critical. To investigate the efficacy of nasal midazolam as an anticonvulsive treatment for OP exposure, as compared to intramuscular midazolam, guinea pigs were connected to a recording swivel for electrocorticograph (ECoG) monitoring and clinical observation. The experimental paradigm consisted of pyridostigmine pretreatment (0.1 mg/kg i.m.) 20 min prior to sarin exposure (1.2x LD(50,) 56 micro g/kg i.m.). One minute post-exposure, atropine (3 mg/kg i.m.) and TMB-4 (1 mg/kg im) were administered. Within 3-8 min after sarin exposure all animals developed electrographic seizure activity (EGSA), with convulsive behavior. Treatment with midazolam (1 mg/kg i.m.) 10 min after the onset of EGSA abolished EGSA within 389+/-181 s. The same dose was not effective, in most cases, when given 30 min after onset. However, a higher dose (2 mg/kg) was found efficacious after 30 min (949+/-466 s). In contrast, nasal application of midazolam (1 mg/kg) was found most effective, with significant advantages, in amelioration of EGSA and convulsive behavior, when given 10 min (216+/-185 s) or 30 min (308+/-122 s) following the onset of EGSA ( P<0.001). Thus, nasal midazolam could be used as a novel, rapid and convenient route of application against seizure activity induced by nerve agent poisoning.

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Histomorphogenesis of Soman-Induced Encephalocardiomyopathy in Sprague-Dawley Rats

Cited by 38 publications

References 60 publications

Early Histopathologic and Ultrastructural Changes in the Heart of Sprague-Dawley Rats Following Administration of Soman

Early Histopathologic and Ultrastructural Changes in the Heart of Sprague-Dawley Rats Following Administration of Soman

Zebrafish is a predictive model for identifying compounds that protect against brain toxicity in severe acute organophosphorus intoxication

Nasal midazolam as a novel anticonvulsive treatment against organophosphate-induced seizure activity in the guinea pig

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