(-)-Huperzine A

(-)-Huperzine A (HupA)是一个乙酰胆碱酯酶(AChE)的抑制剂，IC50值82 nmol/L[1]，也是NMDA受体的拮抗剂[2]。

AChE是负责神经递质乙酰胆碱的快速退化的关键大脑酶。AChE抑制剂在改善阿尔茨海默氏症症状上很可能是有效的[3]。

已发现NMDA可以显著降低AChE活性[4]。在大鼠的海马神经元中，HupA抑制NMDA诱导的电流。在神经元中，HupA为100 μM时，NMDA诱导的电流值相比于对照为55.7 ± 4.9%。NMDA受体：HupA结合的比率为是1:1。HupA对NMDA受体的抑制不是竞争性的[5]。HupA显著增加APPsw过表达细胞中糖原合酶激酶蛋白GSK-3α和GSK-3β的磷酸化水平[2]。激活的GSK-3因此降低纹状体中乙酰胆碱(ACh)水平[6]。

用一定剂量的(-)-huperzine A处理，AChE/老鼠没有表现出任何不良症状，AChE水平正常。这证明了体内AChE抑制剂(-)-huperzine A的特异性[7]。在大鼠全脑中，1.5 μmol/千克的HupA在60分钟时获得最大的抑制性，并且最大抑制性维持了360分钟[8]。

参考文献：
[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.