Increased Permeability of the Hemoencephalic Barrier Produced by Physostigmine and Acetylcholine

Greig, Margaret E.; Holland, William C.

doi:10.1126/science.110.2853.237

Cited by 66 publications

(18 citation statements)

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“…This may be attributed to the inhibition of BuChE and AChE, located in the capillary wall and astrocytes (Koelle, 1952;Joo and Varkonyi, 1969). This suggestion is consistent with the increased permeability of the BBB by PB analog, physostigmine, and ACh (Greig and Holland, 1949).…”

Section: Discussionsupporting

confidence: 88%

Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos

Abou‐Donia¹,

WILMARTH²,

ABDEL-RAHMAN³

et al. 1996

Toxicol Sci

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The operating environment of the service personnel during the Persian Gulf War involved psychological, biological, and chemical elements including exposure to pesticides such as the insect repellent DEET (N.N-diethyl-m-toluamide) and the insecticide chlorpyrifos (0,0-diethyl 0-3,5,6-trichloropyridinyl phosphorothioate) and to pyridostigmine bromide (PB, 3-dimethylaminocarbonyloxy-N-methylpyridinium bromide) that was administered as a prophylactic agent against possible nerve gas attack. The present study was designed to determine the toxicity produced by individual or coexposure of hens 5 days/week for 2 months to 5 mg PB/kg/day in water, by gavage; 500 mg DEET/kg/day, neat, sc; and 10 mg chlorpyrifos kg/day in corn oil, sc. Coexposure to various binary treatments produced greater neurotoxicity than that caused by individual exposures and was characterized by severe neurologic deficit and neuropathological alterations. Also, neurotoxicity was further enhanced following concurrent administration of the three chemicals. Severe inhibition of plasma butyrylcholinesterase (BuChE) activity was produced in hens treated with PB (activity 17% of control) compared to those treated with chlorpyrifos (activity 51% of control) or DEET (activity 83% of control). BuChE inhibition was further increased in binary and tertiary treatment groups compared to individual treatment groups. In contrast, a significant inhibition of brain acetylcholinesterase (AChE) was produced in hens administered chlorpyrifos alone (activity 67% of control), while those given chlorpyrifos in combination with other compounds exhibited a significant inhibition of brain AChE activity ranging from 43 to 76%. Brain neurotoxicity target esterase (NTE) was not inhibited in any of the individual treatment groups or PB/DEET, but was significantly inhibited and had activity expressed as a percentage of control in groups administered combined chlorpyrifos with PB of 73% or DEET of 74% and in the tertiary treatment group of 71%. We hypothesize that test com-' To whom correspondence should be addressed. 2 Present address: ENVIRON Corp., Arlington, VA 22203. pounds may compete for xenobiotic metabolizing enzymes in the liver and blood and may also compromise the integrity of the blood-brain barrier, leading to an increase in their "effective concentrations" in the nervous system to levels equivalent to the toxic doses of individual compounds. This is consistent with the present observation of increases in (1) the inhibition of brain AChE and NTE, (2) the extent of neurologic dysfunction, and (3) the severity and frequency of neuropathologic lesions in the combined treatment groups compared to those administered individual compounds.

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Section: Discussionsupporting

confidence: 88%

Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos

Abou‐Donia¹,

WILMARTH²,

ABDEL-RAHMAN³

et al. 1996

Toxicol Sci

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“…Study of the effect of neostigmine on sodium exchange was prompted by the reports of Greig, Holland and Mayberry (39,40) and Becker and Aird (41) implicating the acetylcholine-cholinesterase system in the control of cerebral permeability. The present study has failed to reveal any 1 705 effect of neostigmine on the permeability of the blood-CSF barrier to sodium.…”

Section: Discussionmentioning

confidence: 99%

Factors Influencing the Exchange of Sodium Between Plasma and Cerebrospinal Fluid*†

Fishman¹

1959

J. Clin. Invest.

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This study is concerned with the mechanism of exchange of sodium between plasma and cerebrospinal fluid (CSF). Several workers (1, 2) have reported that there is no significant difference between the concentration of sodium in plasma and CSF. reported that the average concentration of sodium in CSF, in man, exceeded the plasma concentration by about four mEq. Davson (4) has determined the distribution ratio of sodium between CSF and plasma as 0.975 in the dog, correcting for the difference in water content of these fluids. Despite the similarity in sodium concentration of these fluids and the superficial resemblance of CSF to a protein-free filtrate of plasma, intravenously administered radio-sodium reaches equilibrium in the CSF far more slowly than in the extracellular fluid (5, 6). The delay in exchange between plasma and CSF has been attributed to the existence of a blood-CSF barrier for sodium (5-7). The present experiments have been devised to note the effect of a variety of physiological and pharmacological alterations on the exchange of sodium between these fluid compartments. intervals. The time necessary for the activity of the cisternal fluid to reach 50 per cent of the serum activity was obtained by graphic analysis of the CSF/serum ratios at these time intervals. As the serum radioactivity was not maintained at a constant level, a time constant was not calculated but the half-time as determined was used as the measure of the rate of sodium exchange. This half-time is referred to as the sodium exchange time. A typical experiment is illustrated in Figure 1. Radioactivity was measured in duplicate with a welltype scintillation counter and sodium content with a flame photometer. Each animal had at least one control study in addition to one or more experimental studies. Each animal was given at least a seven day recovery period between experiments. Cisternal fluid pressure, when required, was measured with a spinal water manometer. Blood pressure was recorded in some experiments with a strain-gage manometer. METHODS RESULTSI. Concentration of sodium in serum and cerebrospinal fluid of normal dogs The serum and CSF sodium concentrations were determined in 27 normal dogs. The average serum sodium concentration was 155 ± 6 mEq. per L. The average CSF sodium concentration was 158 + 6 mEq. per L. Statistical analysis using Student's "t" test (8)

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“…Studies carried out in the late 1940's and 1950's indicated that seizures produced by soman and other anticholinesterases also were associated with increased blood-brain barrier permeability (Greig and Mayberry, 1951;Greig and Holland, 1949). However, these earlier studies gave conflicting results due, in part, to outdated methodologies.…”

Section: Approachmentioning

confidence: 70%

Regional Blood-Brain Barrier Responses to Central Cholinergic Activity

Goldman¹,

Berman²

1991

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Increased Permeability of the Hemoencephalic Barrier Produced by Physostigmine and Acetylcholine

Cited by 66 publications

References 0 publications

Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos

Increased Neurotoxicity Following Concurrent Exposure to Pyridostigmine Bromide, DEET, and Chlorpyrifos

Factors Influencing the Exchange of Sodium Between Plasma and Cerebrospinal Fluid*†

Regional Blood-Brain Barrier Responses to Central Cholinergic Activity

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