Disruption of the Blood–Brain Barrier and Neuronal Cell Death in Cingulate Cortex, Dentate Gyrus, Thalamus, and Hypothalamus in a Rat Model of Gulf-War Syndrome

Abdel-Rahman, Ali; Shetty, Ashok K.; Abou‐Donia, Mohamed B.

doi:10.1006/nbdi.2002.0524

Cited by 127 publications

(91 citation statements)

References 86 publications

(96 reference statements)

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“…Because of the specificity of the transportation across the BBB, this effect is expected to be localized and limited but stress could induced heightened sensitivity to ChE inhibitors as previously reported [1,2]. However, such an interaction needs to be demonstrated.…”

Section: Potential Reasons For Changesmentioning

confidence: 91%

“…In one experiment rats exposed to a moderate amount of stress and chemicals including PYR, N-diethyl-m-toluamide (DEET) and permethrin [2] exhibited a significant rupture of the capillaries and BBB damage. The mechanisms inducing damage are not clear and the role of the different chemicals used in co-exposure is rather difficult to appreciate in this experiment.…”

Section: Potential Reasons For Changesmentioning

confidence: 99%

“…The potential mechanisms by which stress could alter the BBB permeability include: (i) activation of vasoactive mediators; (ii) activation of the hypothalamic-pituitary-adrenal axis resulting in the secretion of catecholamines and glucocorticoids; (iii) interaction of catecholamines and glucocorticoids with glutamatergic neurotransmission [5,6]. However, the effects of stress on BBB are rather puzzling and seem, at least, largely dependent on the type and the intensity of stress [2,7]. Many investigations failed to demonstrate any BBB alteration under stress.…”

Section: Introductionmentioning

confidence: 97%

“…Some results showed that exposure to moderate stress and low doses of the chemicals leads to brain injury [2] and it was generally believed that the neurological symptoms displayed by Persian Gulf War veterans could be due to a synergistic interaction of stress with chemicals [2][3][4]. Unexpectedly, a peripheral acting drug such as PYR, a carbamate AChE inhibitor routinely employed in the treatment of myastenia gravis and organophosphates poisoning, was reported to affect central nervous processes under stress [1] through inhibition of brain ChE activity, activation of oncogene and increased neuronal excitability.…”

Section: Introductionmentioning

confidence: 98%

“…In a recent past, attention was focused on the neuropathological effects induced by a combined exposure to stress and a wide variety of chemicals including pesticides, prophylactic drugs such as pyridostigmine (PYR) and the nerve agent sarin [1,2]. Some results showed that exposure to moderate stress and low doses of the chemicals leads to brain injury [2] and it was generally believed that the neurological symptoms displayed by Persian Gulf War veterans could be due to a synergistic interaction of stress with chemicals [2][3][4].…”

Section: Introductionmentioning

confidence: 99%

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Peripheral ChE Inhibition Modulates Brain Monoamines Levels and c-fos Oncogene in Mice Subjected to a Stress Situation

et al. 2005

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The present study examined, in mice, whether regional patterns of brain monoamines concentrations (DA, 5-HT and their metabolites) and expression of c-Fos protein, that may represent a prolonged functional change in neurons, could be changed after a combined exposure to stress and the peripheral cholinesterase reversible inhibitor pyridostigmine (PYR). Animals were subjected every day to a random combination of mild unescapable electric footshocks and immobilization over a 12-day period, resulting in a significant increase of glucocorticoids levels and an activation of c-fos in hippocampus, thalamus and piriform cortex. This stress protocol induced a significant increase of 5-HT levels in striatum, hippocampus and ponto mesencephalic area (PMA) but failed to induce any DA activation. When PYR (0.2 mg/kg s.c. inducing 19-35% inhibition of the plasmatic ChE activity) was administered twice a day during the last 5 days of the stress session, 5-HIAA levels and expression of c-fos oncogene were significantly increased in the most of the brain areas studied. DA levels were also enhanced in striatum/hippocampus as a result of a possible activation of mesolimbic and nigrostriatal dopamine systems. Taken together, these results suggest that a combined exposure to certain stress conditions and PYR leads, in mice, to functional changes in neurons and may affect centrally controlled functions. The mechanisms underlying these modifications and their behavioral implications remain to be further investigated.

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Section: Potential Reasons For Changesmentioning

confidence: 91%

Section: Potential Reasons For Changesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Peripheral ChE Inhibition Modulates Brain Monoamines Levels and c-fos Oncogene in Mice Subjected to a Stress Situation

et al. 2005

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Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

Pall

2009

General, Applied and Systems Toxicology

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Cases of multiple chemical sensitivity (MCS) are initiated by exposure to organic solvents and three classes of pesticides. Each of these can act indirectly to increase NMDA activity and the toxic effects of members of each of these classes can be lowered by using NMDA antagonists. Other chemicals, mercury, H 2 S and CO exposure may also initiate cases of MCS and have toxic responses mediated through increased NMDA activity. Thus each of these types of chemicals appears to act as a toxicant through increased NMDA activity. Six additional types of evidence suggest roles for elevated NMDA activity in MCS, suggesting that this response is involved, not only in MCS case initiation, but also in response to low‐level chemicals in those who are already sensitive. The inference that chemicals act as toxicants in MCS is confirmed by three genetic studies showing that five genes that encode enzymes that metabolize these chemicals act to determine MCS susceptibility. The chronic nature of MCS is thought to be produced by a local biochemical vicious cycle mechanism, the NO/ONOO − cycle, which is initiated by nitric oxide acting through its oxidant product peroxynitrite, which are both produced in MCS in response to excessive NMDA activity. Cycle elements, including NMDA activity, intracellular calcium, nitric oxide and peroxynitrite are thought to interact with other mechanisms, including neural sensitization in the brain and neurogenic inflammation in peripheral tissues to produce the high‐level chemical sensitivity that is the hallmark of MCS. This complex model of MCS is supported by the following types of observations: MCS correlates in the chronic phase of illness, extensive animal model studies implicating almost all NO/ONOO − cycle elements, clinical trial data in the related illnesses chronic fatigue syndrome and fibromyalgia, and a variety of objectively measurable responses to low‐level chemical exposure in MCS patients, responses that should be further studied as possible specific biomarker tests for MCS. While plausible mechanisms are proposed for the generation of both shared and specific symptoms and signs in MCS, there are little data on whether these mechanisms are actually involved in generating these symptoms and signs in MCS. Previous claims that MCS is produced by some sort of psychogenic mechanism have multiple flaws and are inconsistent with the various types of evidence discussed above. Several areas of research are discussed in which the author argues that research will be richly rewarded.

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Pesticides

Abou‐Donia¹

2015

Mammalian Toxicology

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Disruption of the Blood–Brain Barrier and Neuronal Cell Death in Cingulate Cortex, Dentate Gyrus, Thalamus, and Hypothalamus in a Rat Model of Gulf-War Syndrome

Cited by 127 publications

References 86 publications

Peripheral ChE Inhibition Modulates Brain Monoamines Levels and c-fos Oncogene in Mice Subjected to a Stress Situation

Peripheral ChE Inhibition Modulates Brain Monoamines Levels and c-fos Oncogene in Mice Subjected to a Stress Situation

Multiple Chemical Sensitivity: Toxicological Questions and Mechanisms

Pesticides

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