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J.E. Ottenweller, R.J. Servatius, Q.P. Zhu,
D. Beldowicz, and B. H. Natelson
Neurobehavioral Unit, DVA Medical Center, East Orange NJ and
Department of Neurosciences, New Jersey Medical School, Newark NJ
Many soldiers who served in the Persian Gulf took pyridostigmine
bromide (PB) pills as prophylaxis against possible exposure to anticholinergic
nerve agents. Previous research had indicated that there were no persistent
effects of PB after its use was stopped and that it had no anticholinergic
actions in the central nervous system (CNS). However, recent research
by others in mice has suggested that PB may, in fact, inhibit cholinesterase
in the CNS if it is administered immediately after stress. In addition,
our research in rats has indicated that some effects of PB may persist
for or emerge some weeks after PB has been stopped. We administer PB dissolved
in the drinking water for 7 days and have targeted doses in the range
of 1-5 mg/kg/day. We come very close to these doses despite the fact that
we let the rats drink as much as they want to. Depending on body weight,
the recommended PB doses in Gulf soldiers were probably 0.5-1.0 mg/kg/day.
More importantly, our doses of 2 or 5 mg/kg/day produce 15-30% inhibition
of plasma butyrylcholinesterase (BuChE), which is the DoD target for providing
sufficient prophylaxis against nerve agents. We have studied the effects
of PB in Sprague-Dawley (SD) and Wistar-Kyoto (WKY) rats, and we found
that WKY rats have only about half the plasma BuChE as SD rats. We have
also found that acoustic startle responses are normal in WKY rats during
and shortly after 7 days of PB treatment, but exaggerated responses emerge
in PB-treated rats 2-4 weeks after stopping PB. This effect is dose-related,
it is probably due to CNS sensitization to the acoustic stimuli, and it
does not occur in SD rats at the doses we have studied. WKY rats also
show a 0.1-0.3 C increase in core body temperature at the nadir of the
daily temperature rhythm during PB treatment, and this effect unexpectedly
persists for 1-2 weeks after PB treatment has ended. Our data do not address
the issue of whether long-term effects of PB taken during the Gulf War
are contributing to current illness in veterans, but they suggest that
such a possibility can not be dismissed out of hand. If long-term effects
of PB are contributing to illness among Gulf veterans, those who have
low BuChE may have been at greater risk.
KEYWORDS: Pyridostigmine Bromide, Butyrylcholinesterase,
WKY Rats
This work was supported by DVA Medical Research funds and
the DVA New Jersey Center for Environmental Hazards Research. |
