Global changes in the expression patterns of RNA isolated from the hippocampus and cortex of VX exposed mice

Blanton, Jason; D'Ambrozio, Jonathan A.; Sistrunk, James E.; Midboe, Eric G.

doi:10.1002/jbt.20015

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…Oligonucleotide microarrays are commonly used to simultaneously measure the mRNA levels of thousands of genes in a cell and are capable of detecting even subtle changes in gene expression. Gene expression profiling has been successfully used to investigate the mechanisms of toxicity and resulting effects of various CWAs [19-24]. …”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…Indeed, changes in gene expression levels have been reported using regional dissections of the rodent hippocampus. For example, microarray analysis has been used in the hippocampus for a variety of downstream genetic analyses in animal models, including studies of alcohol consumption (Saito et al,2002), aging (Blalock et al,2003), amyloid overexpression (Dickey et al,2003; Reddy et al,2004), antidepressant administration (Drigues et al,2003), epilepsy (Becker et al,2003; Newton et al,2003), hippocampal cytoarchitecture (Zhao et al,2001; Lein et al,2004), hypergravity (Del Signore et al,2004), hypoxia/ischemia (Gilbert et al,2003; Qiu et al,2004), learning and memory (Cavallaro et al,2001,2002), nerve agent exposure (Blanton et al,2004), and traumatic brain injury (Marciano et al,2002), among others. Regional analyses of hippocampal gene expression has also been performed on postmortem human brain tissues, including studies assessing AD (Loring et al,2001; Colangelo et al,2002; Blalock et al,2004; Lukiw,2004) and epilepsy (Becker et al,2002,2003; Lukasiuk and Pitkänen,2004).…”

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confidence: 99%

Expression profile analysis within the human hippocampus: Comparison of CA1 and CA3 pyramidal neurons

Ginsberg

Che

2005

J of Comparative Neurology

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The hippocampus contains several distinct cell types that are interconnected by a well-characterized series of synaptic circuits. To evaluate molecular and cellular signatures of individual cell types within the normal adult human hippocampal formation, expression profile analysis was performed on individual CA1 and CA3 pyramidal neurons using a novel single cell RNA amplification methodology coupled with custom-designed cDNA array analysis. Populations of CA1 and CA3 neurons were also compared with regional dissections of the hippocampus from the same tissue sections. Molecular fingerprint comparison of cresyl violet-stained CA1 and CA3 pyramidal neurons microaspirated from the hippocampus of normal control subjects indicated significant differences in relative expression levels for approximately 16% (20 of 125) genes evaluated on the custom-designed cDNA array platform. Significant differences were observed for several transcripts relevant to the structure and function of hippocampal neurons, including specific glutamate receptors, gamma-aminobutyric acid (GABA) A receptors, cytoskeletal elements, dopamine receptors, and immediate-early genes. Compared with the regional assessment of gene expression, both CA1 and CA3 neurons displayed a relative enrichment of classes of transcripts that included glutamate receptors, transporters, and interacting proteins, GABA receptors and transporters, synaptic-related markers, and catecholamine receptors and transporters. In contrast, the regional hippocampal dissection had an increased level of gene expression for cytoskeletal elements as well as glial-associated markers. Expression profile analysis illustrates the importance of evaluating individual cellular populations within a functional circuit and may help define elements that confer unique properties to individual populations of hippocampal neurons under normal and diseased conditions.

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“…C57BL/6 mice were exposed to low doses (0.2 or 0.4 LD 50 ) of VX five times per week (Monday to Friday) for 2 weeks. Expression of BDNF in mouse brain was measured at 2 or 72 h after the last VX exposure, similar to time points measured by Blanton et al (2004) using microarrays, in which they observed a transient increase in gene clusters following repeated exposure to sublethal doses of VX. In our study, we hypothesized that BDNF levels would be affected by 2 h post-exposure and return to baseline by 72 h post-exposure.…”

mentioning

confidence: 64%

“…there has been minimal research into the molecular mechanisms of exposure to sublethal doses of CWNA, with the exception of Blanton et al (2004), who evaluated the effects of repeated exposure to sublethal doses of VX on neuronal gene expression using microarrays.…”

mentioning

confidence: 99%

Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

Pizarro

Chang

Bah

et al. 2012

Toxicological Sciences

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The highly toxic organophosphorus compound VX [O-ethyl S-[2-(diisopropylamino)ethyl]methylphosphonate] is an irreversible inhibitor of the enzyme acetylcholinesterase (AChE). Prolonged inhibition of AChE increases endogenous levels of acetylcholine and is toxic at nerve synapses and neuromuscular junctions. We hypothesized that repeated exposure to sublethal doses of VX would affect genes associated with cell survival, neuronal plasticity, and neuronal remodeling, including brain-derived neurotrophic factor (BDNF). We examined the time course of BDNF expression in C57BL/6 mouse brain following repeated exposure (1/day × 5 days/week × 2 weeks) to sublethal doses of VX (0.2 LD(50) and 0.4 LD(50)). BDNF messenger RNA expression was significantly (p < 0.05) elevated in multiple brain regions, including the dentate gyrus, CA3, and CA1 regions of the hippocampal formation, as well as the piriform cortex, hypothalamus, amygdala, and thalamus, 72 h after the last 0.4 LD(50) VX exposure. BDNF protein expression, however, was only increased in the CA3 region of the hippocampus. Whether increased BDNF in response to sublethal doses of VX exposure is an adaptive response to prevent cellular damage or a precursor to impending brain damage remains to be determined. If elevated BDNF is an adaptive response, exogenous BDNF may be a potential therapeutic target to reduce the toxic effects of nerve agent exposure.

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Global changes in the expression patterns of RNA isolated from the hippocampus and cortex of VX exposed mice

Cited by 9 publications

References 20 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

Expression profile analysis within the human hippocampus: Comparison of CA1 and CA3 pyramidal neurons

Repeated Exposure to Sublethal Doses of the Organophosphorus Compound VX Activates BDNF Expression in Mouse Brain

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