Preventive effect of Ninjin-yoei-to, a Kampo medicine, on amyloid β(1-42)-induced neurodegeneration via intracellular Zn(2+) toxicity in the dentate gyrus

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer’s disease, here we examined the effect of NYT on amyloid β(1-42) (Aβ(1-42))-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aβ(1-42) was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aβ staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aβ(1-42)-induced increase in intracellular Zn(2+) was reduced, suggesting that pre-administration of NYT prior to Aβ injection is effective for reducing Aβ(1-42)-induced Zn(2+) toxicity in the dentate gyrus. As a matter of fact, Aβ(1-42)-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn(2+)-binding proteins, which can capture Zn(2+) from Zn-Aβ(1-42) complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aβ(1-42)-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn(2+) toxicity induced by Aβ(1-42).