Huperzine A: Is it an Effective Disease-Modifying Drug for Alzheimer's Disease?

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder for which there is no cure. Huperzine A (HupA) is a natural inhibitor of acetylcholinesterase (AChE) derived from the Chinese folk medicine Huperzia serrata (Qian Ceng Ta). It is a licensed anti-AD drug in China and is available as a nutraceutical in the US. A growing body of evidence has demonstrated that HupA has multifaceted pharmacological effects. In addition to the symptomatic, cognitive-enhancing effect via inhibition of AChE, a number of recent studies have reported that this drug has "non-cholinergic" effects on AD. Most important among these is the protective effect of HupA on neurons against amyloid beta-induced oxidative injury and mitochondrial dysfunction as well as via the up-regulation of nerve growth factor and antagonizing N-methyl-d-aspartate receptors. The most recent discovery that HupA may reduce brain iron accumulation lends further support to the argument that HupA could serve as a potential disease-modifying agent for AD and also other neurodegenerative disorders by significantly slowing down the course of neuronal death.

Keywords: Alzheimer’s disease; acetylcholinesterase inhibitor; disease-modifying agent; huperzine A; non-cholinergic effects.

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.