| Scope of study. Since returning from the Persian Gulf War, thousands of U.S. soldiers complained of a variety of unexplained illnesses. Pyridostigmine, a carbamate acetylcholinesterase inhibitor, was used by the U.S. military as a prophylactic agent to protect soldiers from possible organophosphorus nerve agent exposure. The quaternary structure of pyridostigmine limits its entry into the central nervous system. A number of reports suggested, however, that stress may compromise blood-brain barrier integrity and increase pyridostigmine access into the brain. Increased pyridostigmine toxicity in the central nervous system under stressful conditions has been hypothesized to contribute to the development of Gulf War illnesses. We investigated the effects of physical stress (restraint) or chemical stress (paraoxon) on blood-brain barrier permeability to pyridostigmine and possible alterations in pyridostigmine-induced cholinergic toxicity.; Findings and conclusions. Pyridostigmine is a peripheral cholinesterase inhibitor having minimal effects on brain cholinesterase activity. Acute and repeated restraint stress, associated with marked elevations in plasma corticosteroid levels, had little effect on blood-brain barrier permeability to the enzymatic marker horseradish peroxidase, pyridostigmine-induced cholinergic toxicity or cholinesterase inhibition in brain. Pyridostigmine also markedly increased plasma corticosteroid levels. Low dosage paraoxon increased blood-brain barrier leakage to horseradish peroxidase. Paraoxon-induced blood-brain barrier leakage did not, however, facilitate pyridostigmine-induced brain cholinesterase inhibition. Interestingly, pyridostigmine pre-exposure blocked paraoxon-induced blood brain barrier leakage. The current findings, along with a number of studies from other laboratories, suggest that stress has little influence on blood-brain barrier penetration by pyridostigmine or on pyridostigmine-elicited toxicity. Pyridostigmine cannot, however, be completely ruled out as an etiological factor in the development of Gulf War illnesses. |
