Acta Pharmacologica Sinica 2006 September; 27 (9): 1127-1136; doi: 10.1111/j.1745-7254.2006.00411.x

Aim: To investigate the long-term effect of soybean isoflavones on changes in parvalbumin (PV) immunoreactivity in the hippocampus in normal female, ovariectomized (OVX) female and normal male rats.

Methods: Double-probe cerebral microdialysis and HPLC with electrochemical detection were used to detect neurotransmitters.

Results: Our results showed that huperzine A (0.25, 0.5, and 0.75 µmol/kg, po) dose-dependently elevated extracellular acetylcholine (ACh) levels in the medial prefrontal cortex (mPFC) and hippocampus. Oral administration of donepezil (5.4 µmol/kg) or rivastigmine (1 µmol/kg) also elicited significant increases in ACh in the mPFC and hippocampus. The time course of cortical acetylcholinesterase (AChE) inhibition with the 3 inhibitors mirrored the increases of ACh at the same dose. The marked elevation of ACh after oral administration of huperzine A (0.5 µmol/kg) and donepezil (5.4 µmol/kg) was associated with a significantly increased release of dopamine (DA) in the mPFC or hippocampus. None of the 3 inhibitors affected norepinephrine (NE) and 5-hydroxytryptamine (5-HT) levels in the mPFC and hippocampus. The effects of huperzine A and rivastigmine did not depend on the route of administration, but donepezil was less efficacious by the oral route than by ip injection. The ability of huperzine A to increase ACh levels was unchanged when tests were performed after multiple oral administration of the drug at 0.5 µmol/kg, once per day for 30 d.

Conclusion: The present findings showed that, in molar terms, huperzine A had similar potency on increasing mPFC ACh and DA levels as compared to the 11- and 2-fold dosages of donepezil and rivastigmine, respectively, and had longer lasting effects after oral dosing.

Keywords: huperzine A; donepezil; rivastigmine; acetyl-choline; dopamine; norepinephrine; 5-hydroxy tryptamine; Alzheimer's disease; rats