COMPARISON OF THE EFFECTS OF NATURAL AND SYNTHETIC HUPERZINE-A ON RAT-BRAIN CHOLINERGIC FUNCTION IN-VITRO AND IN-VIVO

(-)-Huperzine-A has been shown to be a promising agent for the treatme nt of dementia of the Alzheimer type. This substance is rare in nature . We have been able to prepare a racemic mixture of(+/-)-huperzine-A i n quantity. In the absence of a chiral synthetic procedure for (-)-hup erzine-A, this study sought to determine whether the racemic mixture w ould yield an in vitro and in vivo pharmacological profile of activity similar to that of the natural compound. The synthetic racemic mixtur e (+/-)-huperzine-A was 3 times less potent than (-)-huperzine-A in vi tro (IC50 of 3 x 10(-7) M and 10(-7) M, respectively) because the form er consisted of a racemic mixture of the compound in which the (+)-hup erzine component was considerably less potent (IC50 = 7 x 10(-6) M). A comparable magnitude of effect was also observed in studies conducted in vivo, in which, over a range of 0.1-2.0 mg/kg administered intrape ritoneally (i.p.), both (-)-huperzine-A and (+/-)-huperzine-A exerted significant inhibition of acetylcholinesterase activity, in all brain regions tested (hippocampus, striatum, hypothalamus and frontal cortex ). This inhibition of acetylcholinesterase activity was inversely rela ted to levels of acetylcholine measured in the hippocampus and followe d the same time course of effect, (-)-Huperzine-A and (+/-)-huperzine- A were shown to be more potent than physostigmine as inhibitors of ace tylcholinesterase in vitro (IC50 = 6 X 10(-7) M). Moreover, their inhi bitory effect on acetylcholinesterase in vivo was of a longer duration (peak activity of 20 min for physostigmine versus 60 min for the hupe rzine variants), at the doses tested, Finally, no effect was exerted b y either of the huperzine variants on choline acetyltransferase activi ty in cortex or hippocampus, over a wide range of doses tested (0.1-1. 0 mg/kg, i.p.). These findings demonstrate that (+/-)-huperzine-A comp ares in its activity and biological effects with the natural product, (-)-huperzine-A, both in vitro and in vivo.