Metallothionein synthesis increased by Ninjin-yoei-to, a Kampo medicine protects neuronal death and memory loss after exposure to amyloid β1-42

Abstract

Background: It is possible that increased synthesis of metallothioneins (MTs), Zn²⁺-binding proteins is linked with the protective effect of Ninjin-yoei-to (NYT) on Zn²⁺ toxicity ferried by amyloid β_1-42 (Aβ_1-42).

Methods: Judging from the biological half-life (18-20 h) of MTs, the effective period of newly synthesized MT on capturing Zn²⁺ is estimated to be approximately 2 days. In the present paper, a diet containing 3% NYT was administered to mice for 2 days and then Aβ_1-42 was injected into the lateral ventricle of mice.

Results: MT level in the dentate granule cell layer was elevated 2 days after administration of NYT diet, while the administration reduced intracellular Zn²⁺ level increased 1 h after Aβ_1-42 injection, resulting in rescuing neuronal death in the dentate granule cell layer, which was observed 14 days after Aβ_1-42 injection. Furthermore, Pre-administration of NYT diet rescued object recognition memory loss via affected perforant pathway long-term potentiation after local injection of Aβ_1-42 into the dentate granule cell layer of rats.

Conclusion: The present study indicates that pre-administration of NYT diet for 2 days increases synthesis of MTs, which reduces intracellular Zn²⁺ toxicity ferried by extracellular Aβ_1-42, resulting in protecting neuronal death in the dentate gyrus and memory loss after exposure to Aβ_1-42.

Keywords: Alzheimer’s disease; Amyloid β1-42; Kampo medicine; Metallothionein; Ninjin-yoei-to; Zn2+ dysregulation.