Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman

Myhrer, Trond; Enger, Siri; Aas, Pål

doi:10.1016/j.neuro.2007.03.010

Cited by 24 publications

(8 citation statements)

References 34 publications

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“…Using our exposure model, roughly 50% of the sarin-exposed animals developed seizure activity with a mean latency of 10.2 min, as indicated by behavioral assessment and electrocortical activity. In this study, we analyzed gene expression changes in the piriform cortex of seizing animals because it has been identified as one of the regions in the central nervous system to show massive, early-onset tissue pathology following nerve agent-induced seizures [10,13,25]. In agreement with previous studies [6,15,26,28,36], we found major gene expression profile differences correlated with seizure induction and identified a strong inflammatory response that could potentially lead to brain injury and cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, antagonism of pro-inflammatory molecules, as well as their receptors and signaling pathways, may represent a new approach for the development of additional therapies to better protect the brain against seizure-induced damage. Several seizure-inducing sites have been identified within the piriform cortex [10,13,25], so it seems logical to focus on the molecular alterations in this brain region to help identify these potential molecular targets. Because current countermeasures may not fully prevent neurological damage, this type of in-depth analysis is critical to examine the molecular effects following nerve agent exposure and identify therapeutics that can reduce or block the cascade of secondary events that lead to neuropathology and associated functional impairments.…”

Section: Discussionmentioning

confidence: 99%

“…We performed gene expression profiling of the piriform cortex, one of the regions in the central nervous system to show massive early-onset tissue pathology from nerve agent-induced seizures [10,13,25], following sarin exposure in a rat model to identify the molecular effects involved in nerve agent-induced neurodegeneration. In the present manuscript, we have focused on the transcriptional responses observed in sarin-exposed seizing animals.…”

Section: Introductionmentioning

confidence: 99%

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Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Spradling¹,

Lumley²,

Robison³

et al. 2011

J Neuroinflammation

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BackgroundOrganophosphorus nerve agents irreversibly inhibit acetylcholinesterase, causing a toxic buildup of acetylcholine at muscarinic and nicotinic receptors. Current medical countermeasures to nerve agent intoxication increase survival if administered within a short period of time following exposure but may not fully prevent neurological damage. Therefore, there is a need to discover drug treatments that are effective when administered after the onset of seizures and secondary responses that lead to brain injury.MethodsTo determine potential therapeutic targets for such treatments, we analyzed gene expression changes in the rat piriform cortex following sarin (O-isopropyl methylphosphonofluoridate)-induced seizure. Male Sprague-Dawley rats were challenged with 1 × LD50 sarin and subsequently treated with atropine sulfate, 2-pyridine aldoxime methylchloride (2-PAM), and the anticonvulsant diazepam. Control animals received an equivalent volume of vehicle and drug treatments. The piriform cortex, a brain region particularly sensitive to neural damage from sarin-induced seizures, was extracted at 0.25, 1, 3, 6, and 24 h after seizure onset, and total RNA was processed for microarray analysis. Principal component analysis identified sarin-induced seizure occurrence and time point following seizure onset as major sources of variability within the dataset. Based on these variables, the dataset was filtered and analysis of variance was used to determine genes significantly changed in seizing animals at each time point. The calculated p-value and geometric fold change for each probeset identifier were subsequently used for gene ontology analysis to identify canonical pathways, biological functions, and networks of genes significantly affected by sarin-induced seizure over the 24-h time course.ResultsA multitude of biological functions and pathways were identified as being significantly altered following sarin-induced seizure. Inflammatory response and signaling pathways associated with inflammation were among the most significantly altered across the five time points examined.ConclusionsThis analysis of gene expression changes in the rat brain following sarin-induced seizure and the molecular pathways involved in sarin-induced neurodegeneration will facilitate the identification of potential therapeutic targets for the development of effective neuroprotectants to treat nerve agent exposure.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Spradling¹,

Lumley²,

Robison³

et al. 2011

J Neuroinflammation

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“…To understand the mechanism of seizures, previous studies (Spradling et al, 2011a(Spradling et al, , 2011b have analyzed the transcriptomic responses in five nerve agent-sensitive brain regions (Aroniadou-Anderjaska et al, 2009;Myhrer, 2007;Myhrer et al, 2007) at different time intervals (0.25 h, 1 h, 3 h, 6 h, and 24 h) in rats following sarin-induced seizures. In these experiments, approximately half of the rats exposed to a 1 Â LD 50 (median lethal dose) concentration of sarin developed seizures (Fig.…”

Section: Introductionmentioning

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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“…The in vitro experiments were performed in the BLA because, in addition to the importance of other brain regions in seizure generation by OPs (Myhrer, 2007;Myhrer et al, 2007Myhrer et al, , 2010, there is strong evidence to suggest that the BLA plays a key role ). Thus, when McDonough et al (1987) microinjected nerve agents into different brain regions, they observed that convulsions were elicited only when the nerve agent was injected into the BLA.…”

Section: Discussionmentioning

confidence: 99%

The M₁ Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

Miller

Aroniadou‐Anderjaska

Pidoplichko

et al. 2016

J Pharmacol Exp Ther

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Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M 1 receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M 1 receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon-namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current I h in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M 1 antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive.

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Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman

Cited by 24 publications

References 34 publications

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Neuroprotective mechanisms activated in non-seizing rats exposed to sarin

The M₁ Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

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Anticonvulsant effects of damage to structures involved in seizure induction in rats exposed to soman

Cited by 24 publications

References 34 publications

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Transcriptional analysis of rat piriform cortex following exposure to the organophosphonate anticholinesterase sarin and induction of seizures

Neuroprotective mechanisms activated in non-seizing rats exposed to sarin

The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

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The M₁ Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala