Huperzine A CAS 102518-79-6

Huperzine A has a highly selective inhibitory effect on acetylcholinesterase, thereby reducing the hydrolysis of acetylcholine, and by activating N receptors or M receptors on presynaptic membranes and antagonizing M receptors on postsynaptic membranes, choline Enhanced functionality. In addition, by supplementing acetylcholine precursors, the synthesis of acetylcholine is increased, and the cholinergic neurons are excited, thereby enhancing the learning and memory ability of AD patients and improving the cognitive and behavioral function. There are various molecular subtypes of acetylcholinesterase. There are G4 and G1 types in the mammalian brain. G4 type is the main type, and about 60% to 90% are distributed in the extracellular fluid of nerves, especially in the synaptic space.

Zhao et al. compared the inhibitory effects of huperzine A, tacrine, donepezil, rivastigmine and physostigmine on different subtypes of AChE in rat intracranial cortex, hippocampus and striatum. The inhibitory effect of A on G4-type acetylcholinesterase is significantly stronger than that of G1-type, that is, Huperzine A has a higher affinity for G4-type. It can be seen that Huperzine A can fully inhibit acetylcholinesterase in the synaptic cleft of acetylcholinergic neurons, increase the concentration of acetylcholine, and has a more obvious improvement effect on cognitive impairment and memory loss in AD patients.

Aβ is mainly toxic to nerve cells through oxidative stress, resulting in apoptosis of the latter. Hong Sijia et al. found that in brain autopsy of AD patients, lipid peroxidation in brain regions such as hippocampus piriform nucleus and amygdala was significantly increased, and the activities of superoxide dismutase and catalase were significantly decreased. Zhang et al. found that huperzine A can improve neuronal cell survival and anti-peroxidase (such as glutathione peroxidase, superoxide dismutase, peroxidase) activities, while reducing malondialdehyde and other lipid peroxidation products. It is suggested that the anti-Aβ neurotoxicity of Huperzine A is mainly achieved by increasing the anti-peroxidase activity.

There are two main pathways for the metabolism of APP. One is the non-amyloidogenic pathway, that is, α-secretase and γ-secretase decompose APP to produce membrane-bound APP (CTF-C83) and soluble APP (sAPPα). CTF-C83 contains Aβ sequence, sAPPα has neuroprotective and trophic activity, can effectively promote cell proliferation, axonal growth, inhibit cell damage caused by intracellular calcium overload, and help delay the progression of AD damage; the second is amyloidosis The pathway, namely β-secretase and γ-secretase, cleaves APP to produce Aβ.

Studies have shown that acetylcholine activates the intracellular PLC-PKC signaling pathway by binding to M1-type or M3-type acetylcholine receptors, and tyrosine phosphorylated by PKC activates α-secretase and increases sAPPα secretion [6]. Cell model experiments have shown that Huperzine A activates the PKC signaling pathway, activates α-secretase, promotes the decomposition of APP in a non-amyloidogenic manner to generate sAPPα, and inhibits the production of Aβ. This is related to the fact that Huperzine A binds to the surrounding sites of acetylcholinesterase, interferes with the formation of the complex between acetylcholinesterase and Aβ, and reduces the toxicity mediated by Aβ.

Shi Qinghai et al. found that Huperzine A can alleviate the apoptosis of hippocampal neurons in the rat brain caused by acute hypotension and hypoxia by down-regulating the expression of the pro-apoptotic factor Bax and up-regulating the expression of the anti-apoptotic factor Bcl-2 in the hippocampus. , can improve the spatial learning and memory ability of model rats.