Metallothionein synthesis increased by Ninjin-yoei-to, a Kampo medicine protects neuronal death and memory loss after exposure to amyloid ß1-42.

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 ß1-42 (Aß1-42). 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 Aß1-42 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 Aß1-42 injection, resulting in rescuing neuronal death in the dentate granule cell layer, which was observed 14 days after Aß1-42 injection. Furthermore, Pre-administration of NYT diet rescued object recognition memory loss via affected perforant pathway long-term potentiation after local injection of Aß1-42 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 Aß1-42, resulting in protecting neuronal death in the dentate gyrus and memory loss after exposure to Aß1-42.

Isoproterenol injected into the basolateral amygdala rescues amyloid ß1-42-induced conditioned fear memory deficit via reducing intracellular Zn2+ toxicity.

On the basis of amyloid ß (Aß) peptides as triggers in atrophy of structures in the limbic system, here we postulated that Aß1-42-induced intracellular Zn2+ toxicity in the basolateral amygdala contributes to conditioned fear memory. Aß1-42 increased intracellular Zn2+ level in the amygdala after local injection of Aß1-42 into the basolateral amygdala, resulting in conditioned fear memory deficit via attenuated LTP at perforant pathway-basolateral amygdala synapses. Co-injection of isoproterenol, a beta-adrenergic receptor agonist, reduced Aß1-42-mediated increase in intracellular Zn2+, resulting in rescue of the memory deficit and attenuated LTP. The present study suggests that beta-adrenergic activity induced by isoproterenol in the basolateral amygdala rescues the impairment of conditioned fear memory by Aß1-42. The rescuing effect may be linked with reducing Aß1-42-induced intracellular Zn2+ toxicity. Furthermore, Aß1-42 injection into the basolateral amygdala also attenuated LTP at perforant pathway-dentate granule cell synapses, while co-injection of isoproterenol rescued it, suggesting that Aß1-42 toxicity in the basolateral amygdala also affects hippocampus-dependent memory. It is likely that beta-adrenergic receptor activation in the basolateral amygdala rescues the limbic system exposed to Aß1-42 toxicity.