Dehydroeffusol Pprevents Amyloid β_1-42-mediated Hippocampal Neurodegeneration via Reducing Intracellular Zn²⁺ Toxicity

Abstract

Dehydroeffusol, a phenanthrene isolated from Juncus effusus, is a Chinese medicine. To explore an efficacy of dehydroeffusol administration for prevention and cure of Alzheimer’s disease, here we examined the effect of dehydroeffusol on amyloid β_1-42 (Aβ_1-42)-mediated hippocampal neurodegeneration. Dehydroeffusol (15 mg/kg body weight) was orally administered to mice once a day for 6 days and then human Aβ_1-42 was injected intracerebroventricularly followed by oral administration for 12 days. Neurodegeneration in the dentate granule cell layer, which was determined 2 weeks after Aβ_1-42 injection, was rescued by dehydroeffusol administration. Aβ staining (uptake) was not reduced in the dentate granule cell layer by pre-administration of dehydroeffusol for 6 days, while increase in intracellular Zn²⁺ induced with Aβ_1-42 was reduced, suggesting that pre-administration of dehydroeffusol prior to Aβ_1-42 injection is effective for Aβ_1-42-mediated neurodegeneration that was linked with intracellular Zn²⁺ toxicity. As a matter of fact, pre-administration of dehydroeffusol rescued Aβ_1-42-mediated neurodegeneration. Interestingly, pre-administration of dehydroeffusol increased synthesis of metallothioneins, intracellular Zn²⁺-binding proteins, in the dentate granule cell layer, which can capture Zn²⁺ from Zn-Aβ_1-42 complexes. The present study indicates that pre-administration of dehydroeffusol protects Aβ_1-42-mediated neurodegeneration in the hippocampus by reducing intracellular Zn²⁺ toxicity, which is linked with induced synthesis of metallothioneins. Dehydroeffusol, a novel inducer of metallothioneins, may protect Aβ_1-42-induced pathogenesis in Alzheimer’s disease.