The Therapeutic Effects of Seven Lycopodium Compounds on Cell Models of Alzheimer’s Disease

Article type: Research Article

Authors: Guo, Qian^{a; b; 1} | Cai, Qinfeng^{c; 1} | Huang, Fang^a | Wei, Zhen^a | Wang, Jian-Zhi^{a; b} | Zhang, Bin^a | Liu, Rong^a | Yang, Yang^{d; *} | Wang, Xiaochuan^{a; b; e; *} | Li, Hong-Lian^{a; *}

Affiliations: [a] School of Basic Medicine, Key Laboratory of Education Ministry/Hubei Province of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [b] Co-innovation Center of Neuroregeneration, Nantong University, Nantong, JS, China | [c] School of Mental Health and Psychological Science, Anhui Medical University, Hefei, Anhui, China | [d] Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, China | [e] Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, China

Correspondence: [*] Hong-Lian Li, PhD, Professor, Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel.: +86 27 83692612; E-mail: [email protected]; Xiaochuan Wang, PhD, Professor, Department of Pathophysiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel.: +86 27 83692625; Fax: +86 27 83693883; E-mail: [email protected]; Yang Yang, PhD, Professor, Hubei Key Laboratory of Natural Medicinal Chemistry and Resource Evaluation, School of Pharmacy, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. E-mail: [email protected].

Note: [1] These authors contributed equally to this work.

Abstract: Background:As an acetylcholinesterase inhibitor (AChEI), Huperzine-A (Hup-A) is marketed for treatment of mild to moderate Alzheimer’s disease (AD) for decades in China. However, Hup-A causes some side effects. To search for new analogs or derivatives of Hup-A, we produced five Lycopodium alkaloids and two analogues by chemical synthesis: Lyconadins A-E, H-R-NOB, and 2JY-OBZ4. Objective:To systematically evaluate the therapeutic effects of the seven compounds on AD cell models. Methods:We assessed the effects of the seven compounds on cell viability via CCK-8 kit and used HEK293-hTau cells and N2a-hAPP cells as AD cell models to evaluate their potential therapeutic effects. We examined their effects on cholinesterase activity by employing the mice primary neuron. Results:All compounds did not affect cell viability; in addition, Lyconadin A and 2JY-OBZ4 particularly increased cell viability. Lyconadin D and Lyconadin E restored tau phosphorylation at Thr231, and H-R-NOB and 2JY-OBZ4 restored tau phosphorylation at Thr231 and Ser396 in GSK-3β-transfected HEK293-hTau cells. 2JY-OBZ4 decreased the level of PP2Ac-pY307 and increased the level of PP2Ac-mL309, supporting that 2JY-OBZ4 may activate PP2A. Lyconadin B, Lyconadin D, Lyconadin E, H-R-NOB, and 2JY-OBZ4 increased sAβPPα level in N2a-hAPP cells. 2JY-OBZ4 decreased the levels of BACE1 and sAβPPβ, thereby reduced Aβ production. Seven compounds exhibited weaker AChE activity inhibition efficiency than Hup-A. Among them, 2JY-OBZ4 showed the strongest AChE inhibition activity with an inhibition rate of 17% at 10μM. Conclusion:Among the seven Lycopodium compounds, 2JY-OBZ4 showed the most expected effects on promoting cell viability, downregulating tau hyperphosphorylation, and Aβ production and inhibiting AChE in AD.

Keywords: Alzheimer’s disease, beta-Secretase 1, cholinesterase inhibitor, Lycopodium alkaloid, protein phosphatase-2A

DOI: 10.3233/JAD-220704

Journal: Journal of Alzheimer's Disease, vol. 90, no. 2, pp. 795-809, 2022