Huperzine A (HUP) is a naturally-occurring, potent, reversible inhibit
or of acetylcholinesterase (AChE) that crosses the blood-brain barrier
. To examine its ability to protect against nerve agent poisoning, HUP
was administered i.p. to mice, and the s.c. LD(50) of soman was deter
mined at various time intervals after pretreatment. Results were compa
red to those obtained for animals treated with physostigmine. A protec
tive ratio of approximately 2 was maintained for at least 6 hr after a
single injection of HUP, without the need for any post-challenge drug
therapy. By contrast, pretreatment with physostigmine increased the L
D(50) of soman by 1.4- to 1.5-fold for only up to 90 min. The long-las
ting antidotal efficacy displayed by HUP correlated with the time cour
se of the blood-AChE inhibition. The results suggest that the protecti
on of animals by HUP from soman poisoning was achieved by temporarily
sequestering the active site region of the physiologically important A
ChE.