Figure 1.

A summary of pharmacological mechanisms of huperzine A (HupA) in the treatment of Alzheimer’s disease (AD). In addition to acting as an acetylcholinesterase (AchE) inhibitor, HupA has non-cholinergic roles in the treatment of AD to protect neurons and other brain cells from oxidative stress damage and apoptosis. It has been demonstrated that HupA has the ability: (1) to protect neurons against Aβ-induced oxidative injury and apoptosis by enhancing the activities of antioxidant enzymes including glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and catalase (CAT), attenuating the Aβ-induced increase in caspase-3 activity, and inhibiting Aβ-induced apoptosis by reversing the down-regulation of the expression of Bcl-2 and the up-regulation of Bax and p53 expressions; (2) to ameliorate mitochondrial malfunction in AD brain by preventing Aβ-penetration into the mitochondria, suppressing ROS production, and improving mitochondrial integrity and energy metabolism, thus minimizing Aβ-induced mitochondrial malfunction; (3) to act as antagonist of the NMDA receptors (NMDA-R) to inhibit the NMDA-induced toxicity by blocking NMDA ion channels and the subsequent Ca²⁺ mobilization; (4) to increase nerve growth factor (NGF), which protects basal forebrain cholinergic neurons (BFCNs) from both traumatic insults and age-related cholinergic decline and regulate both amyloid gene expression and protein processing and counteract tau hyperphosphorylation, acting directly at the two classical hallmarks of AD; (5) to promote non-amyloidogenic processing by activating protein kinase C (PKC) and the Wnt/β-catenin signaling pathway; and (6) to inhibit transferrin receptor 1 (TfR1) expression and then reduce transferrin-bound iron (TBI) uptake by the neurons or other brain cells, which have TfR1 expression on the membrane, leading to a progressive reduction in iron contents and also iron-induced oxidative stress in the brain. Based on these roles, it is reasonable to consider HupA as an effective disease-modifying drug for AD. (+) = stimulate; (−) = inhibit; ↑ = increase; ↓ = decrease; Ach = acetylcholine.