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ToxSci Advance Access originally published online on February 19, 2004
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Toxicological Sciences 78, 241-247 (2004)
Toxicological Sciences vol. 78 no. 2 © Society of Toxicology; all rights reserved.

Interactive Effects of Paraoxon and Pyridostigmine on Blood-Brain Barrier Integrity and Cholinergic Toxicity

Xun Song*, Carey Pope*, Ramesh Murthy{dagger}, Jamaluddin Shaikh*, Bachchu Lal{dagger} and Joseph P. Bressler{dagger},{ddagger},1

* Neurotoxicology Laboratory, Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, Oklahoma 74078; {dagger} Kennedy Krieger Institute and {ddagger} Department of Environmental Health Sciences, School of Public Health, Johns Hopkins University, Baltimore, Maryland 21205

Received October 8, 2003; accepted January 10, 2004

The effect of the organophosphorous insecticide paraoxon on the integrity of the blood-brain barrier (BBB) and permeability of pyridostigmine (PYR), a peripheral inhibitor of cholinesterase activity, was examined in Long Evans rats. The integrity of the BBB was examined by measuring the number of capillaries leaking horseradish peroxidase, which was injected into the heart. Treatment with paraoxon at 100 µg/kg, intramuscularly, resulted in a 3- to 4-fold increase in the number of leaky capillaries in young rats (25 to 30 days old) but not in older rats (90 days old). Interestingly, young rats treated with PYR (30 mg/kg, po) 50 min before treatment with paraoxon showed an inhibited effect of paraoxon on the BBB. Furthermore, no increase in the degree of inhibition of acetylcholinesterase activity was observed in young rats treated with PYR before paraoxon compared with young rats treated with paraoxon alone. Cholinergic toxicity, as assessed by changes in behavior, was not observed in young rats treated with paraoxon alone; but, slight signs of cholinergic toxicity were observed in rats treated with PYR. Young rats treated with both PYR and paraoxon did not exhibit more extensive signs of toxicity than rats treated with paraoxon alone or PYR alone. The results indicate that treatment with paraoxon can compromise BBB permeability at dosages that do not induce cholinergic toxicity, but only in young rats. Also, PYR pre-exposure appears to protect the BBB from the paraoxon-induced alterations.

Key Words: paraoxon; pyridostigmine bromide; blood-brain barrier; cholinesterase; Gulf War illness.


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