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ToxSci Advance Access published online on February 19, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh076
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received October 8, 2003; accepted January 10, 2004
© 2004 Society of Toxicology

Neurotoxicology

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

Xun Song 1, Carey Pope 1, Ramesh Murthy 2, Jamaluddin Shaikh 1, Bachchu Lal 2, and Joseph P. Bressler 3*

1 Neurotoxicology Laboratory, Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078
2 Kennedy Krieger Institute, School of Public Health, Johns Hopkins University, Baltimore, MD, 21205
3 Kennedy Krieger Institute, School of Public Health, Johns Hopkins University, Baltimore, MD, 21205; Department of Environmental Health Sciences, School of Public Health, Johns Hopkins University, Baltimore, MD, 21205

* To whom correspondence should be addressed. E-mail: bressler{at}kennedykrieger.org.


  Abstract

The effect of the organophosphorous insecticide paraoxon on the integrity of the blood brain barrier (BBB) and permeability of pyridostigmine, 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 3-4 fold increase in the number of leaky capillaries in young rats, 25 to 30 day-old, but not in older rats at 90 days-old. Interestingly, young rats treated with pyridostigmine (30 mg/kg, po), at 50 minutes before paraoxon, inhibited the effect of paraoxon on the BBB. Furthermore, no change in the degree of inhibition of acetylcholinesterase activity was observed in young rats treated with pyridostigmine before treatment with paraoxon compare to 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 pyridostigmine. Young rats treated with both pyridostigmine and paraoxon did not exhibit more extensive signs of toxicity than rats treated with paraoxon alone or pyridostigmine alone. The results indicate that treatment with paraoxon can compromise BBB permeability at dosages that do not induce cholinergic toxicity, but only in younger rats. Also, pyridostigmine pre-exposure appears to protect the BBB from the paraoxon-induced alterations.

Key Words: Paraoxon, pyridostigmine bromide, blood-brain barrier, cholinesterase, and Gulf War illness .


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