Home Journal Excerpts Gulf War Syndrome Disruption of the Blood-Brain Barrier and Neuronal Cell Death in Cingulate Cortex
Disruption of the Blood-Brain Barrier and Neuronal Cell Death in Cingulate Cortex PDF Print E-mail
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Tuesday, 01 January 2002 00:00
“Many Persian Gulf War (PGW) veterans have complained of illnesses affecting the nervous and musculoskeletal systems. These include chronic fatigue, muscle pain, brain abnormalities, ataxia, inability to concentrate, forgetfulness, and behavioral symptoms. During the PGW, the veterans were exposed to a combination of biological, psychological, chemical, and stressful environments. To begin with, to protect against the potential exposure to biological and chemical weapons, the United States and other troops received anthrax vaccine, botulinum toxin vaccine, and 21 tablets of pyridostigmine bromide (PB). The drug PB was employed as a prophylactic treatment to protect against organophosphate nerve agents. Second, chemical sensors and alarms employed throughout the region as warning devices to chemical and biological attacks were psychologically challenging, as they were extremely sensitive and could be triggered by organic solvents, vehicle exhaust fumes, insecticides, and chemical warfare agents. Third, pesticides were widely used by troops to combat the ubiquitous insect and rodent populations in the region. The pesticides include organophosphate chemicals, the insect repellent N,N-diethyl-m-toluamide (DEET), and the insecticide permethrin. In light of the above pattern of exposure experienced by the troops during the PGW, it is generally believed that the neurological symptoms displayed by PGW veterans are due to a synergistic interaction of PB with other chemicals such as DEET and permethrin and the stress.”

“The drug PB is a reversible cholinesterase inhibitor commonly used for the treatment of myasthenia and as prophylactic protection against organophosphate nerve agents. … an overdose of PB can cause apoptotic cell death in selected brain regions and mitochondrial damage in pre- and postsynaptic regions of the neuromuscular junction.”

“The chemical DEET is the most commonly used insect repellant. … The symptoms associated with DEET poisoning are characterized by tremors, restlessness, difficulty in speech, seizures, impairment of cognitive function, and coma. Extremely high levels of DEET exposure have been reported to cause spongiform myelinopathy. Its insecticidal activity persists for several weeks following a single application.”

“Permethrin intoxication results as a consequence of the sustained opening of sodium channels leading to repetitive discharges after a single stimulus. This repetitive nerve action is associated with tremor, hyperactivity, ataxia, convulsions, and, in some cases, paralysis.”

“Stress is a common experience of daily life and all organisms have evolved mechanisms and strategies to deal with crucial alterations in their internal and external environment. A limited stress can actually exert beneficial effects on the brain function, particularly the promotion of plasticity and the enhancement of learning and memory performance. However, a persistent and higher degree of stress can cause deleterious effects on the brain including the disruption of the BBB [Blood Brain Barrier].”

“Thus, exposure to drugs and chemicals under stressful conditions is highly detrimental to the CNS [Central Nervous System].”

“… the development of Gulf War syndrome is likely due to a combined exposure to multiple factors such as the chemicals DEET, permethrin, and PB and stress. Our earlier studies demonstrate that sub-chronic exposure to DEET and permethrin causes significant pathological changes in the brain, and a concurrent exposure to large doses of PB, DEET, and permethrin results in increased neurotoxicity.”

“The animals treated with both stress and chemicals PB, DEET, and permethrin showed a significant weight loss compared to the vehicle-treated control animals.”

“The measurement of surviving and dying neurons per square millimeter of tissue in different brain regions revealed a significant reduction in the density of surviving neurons and a significant number of dying neurons in animals tested with both stress and chemicals. However, the density of surviving and dying neurons in animals treated with either stress or chemicals alone was comparable to that of vehicle treated control animals. In comparison to vehicle-treated control animals, the density of surviving neurons in animals treated with both stress and chemicals exhibited a 36% decrease in the cingulated cortex (P < 0.01), a 40% decrease in the dentate granule cell layer (P < 0.001), a 30% decrease in the lateral dorsal nucleus of the thalamus, and a 40% decrease in the dorsomedial nucleus of the hypothalamus (P < 0.01). Animals treated with a combination of stress and chemicals also exhibited a significant number of dying neurons in all of the above brain regions, in comparison to animals in other groups (P < 0.001). Thus quantitative analyses of both surviving and dying neurons clearly demonstrate a significant loss of neurons with exposure to a combination of stress and chemicals but no loss of neurons with exposure to either stress or chemicals alone.”

“Previous studies have shown that exposure to higher doses of PB, DEET, and permethrin, alone or in combination, or subchronic exposure to lower doses of DEET and permethrin leads to significant brain damage, characterized by neurological dysfunction, neuropathology, and behavioral abnormalities. In addition, several studies suggest that synergistic effects of low doses of PB, DEET, and permethrin lead to significantly decreased locomotor activity in both male and female rats. The present results indicate that a combination of the stress and lower doses of chemicals PB, DEET, and permethrin induces a significant neuronal cell death in all brain regions where BBB [Blood Brain Barrier] was also disrupted.”

“There have been two different hypotheses for the basis of Gulf War syndrome, one of which is focused predominantly on "stress" as the cause, whereas the other theory that Gulf War syndrome is a result of exposure to a wide variety of chemicals including pesticides, the prophylactic drug PB, other experimental vaccines, depleted uranium, and the nerve gas sarin. In this study, using adult rats, we rigorously investigated the neuropathological effects of a combined exposure to a moderate level of stress and low doses of selected chemicals (PB, DEET, and permethrin) to which PGW veterans were believe to be exposed during the PGW. In addition, the route of exposure and dose levels of test compounds in this study were approximately equivalent to the exposure that may have occurred to army personal during the Gulf War. Our results reveal that a combined exposure to stress and chemicals causes both disruptions of the BBB and neuronal cell death in many regions of the brain. This is in great contrast to animals exposed to either stress or chemical alone, which remain mostly comparable to vehicle-treated control animals. These results underscore that combined exposure to moderate stress and low doses of chemicals PB, DEET, and permethrin leads to a significant brain injury. In this context, it is likely that the various neurological symptoms (such as memory loss, dizziness, impaired sense of direction, depression, and amyotrophic lateral sclerosis) reported by PGW veterans is, at least, partially linked to this kind of brain injury incurred during the war.”


Ali Abdel-Rahman; Ashok K. Shetty; and Mohamed B. Abou-Donia, "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", Neurobiology of Disease, January 1, 2002, Vol. 10, Num. 0, pp. 306-326

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