(?)-Huperzine A (HupA) is an acetylcholinesterase (AChE) inhibitor with an IC50 value of 82 nmol/L [1] and acts as an antagonist of the N-methyl-d-aspartate (NMDA) receptor [2].

AChE is the key brain enzyme responsible for the rapid degradation of the neurotransmitter acetylcholine. AChE inhibitors are probably useful in the amelioration of the Alzheimer’s symptomatology [3].

It was found that NMDA markedly reduced AChE activities [4]. In rat dissociated hippocampal neurons, HupA inhibited the NMDA-induced current. In neurons, 100 μM HupA, NMDA-induced currents were 55.7 ± 4.9% of the control values. The binding molecular ratio of NMDA receptor: HupA is 1:1. The inhibition of NMDA receptor by HupA is not competitive [5]. HupA significantly increased the phosphorylation levels of both glycogen synthase kinase (GSK)-3α protein and GSK-3β protein in APPsw-overexpressing cells [2]. Activated GSK-3 consequently decreased acetylcholine (ACh) level in the striatum [6].

Treated with doses of (?)-huperzine A, AChE?/? mice showed no toxic symptoms and had normal levels of AChE. This demonstrated the specificity of (?)-huperzine A as an inhibitor of AChE at the dose used in vivo [7]. In rat whole brain, oral administration of HupA at a dose of 1.5 μmol/kg (3.6 mg/kg) obtained a maximum inhibition of AChE at 60 min and this maximum inhibition was maintained for 360 min [8].

References:
[1].  MA Xiao-Chao, XIN Jian, WANG Hai-Xue, et al. Acute effects of huperzine A and tacrine on rat liver. Acta Pharmacol ogica Sinica, 2003, 24(3):247-250.
[2].  Zhong Ming Qian and Ya Ke. Huperzine A: is it an effective disease-modifying drug for Alzheimer's disease? Frontiers in Aging Neuroscience, 2014, 6:216.
[3].  V. Rajendran, Suo-Bao Rong, Ashima Saxena, et al. Synthesis of a hybrid analog of the acetylcholinesterase inhibitors huperzine A and huperzine B. Tetrahedron Letters, 2001, 42: 5359-5361.
[4].  J. R. Delfs, D. M. Saroff, Y. Nishida, et al. Effects of NMDA and its antagonists on ventral horn cholinergic neurons in organotypic roller tube spinal cord cultures. J. Neural Transm., 1997, 104(1):31-51.
[5].  J. M. Zhang and G. Y. Hu. Huperzine A, a nootropic alkaloid, inhibits N-methyl-D-aspartate-induced current in rat dissociated hippocampal neurons. Neuroscience, 2001, 105(3):663-9.
[6].  L. Zhao, C. B. Chu, J. F. Li, et al. Glycogen synthase kinase-3 reduces acetylcholine level in striatum via disturbing cellular distribution of choline acetyltransferase in cholinergic interneurons in rats. Neuroscience, 2013, 255:203-11.
[7].  Ellen G. Duysen, Bin Li, Sultan Darvesh, et al. Sensitivity of butyrylcholinesterase knockout mice to (?)-huperzine A and donepezil suggests humans with butyrylcholinesterase deficiency may not tolerate these Alzheimer’s disease drugs and indicates butyrylcholinesterase function in neurotransmission. Toxicology, 2007, 233:60-69.
[8].  Rui Wang, Han Yan and Xi-can Tang. Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine. Acta Pharmacologica Sinica, 2006, 27:1-26.