N-acetyl-5-methoxykynuramine enhance object location and working memory performances via modulating CaMKII, ERK and CREB phosphorylation

Melatonin (MEL) has been reported to enhance cognitive performance. Recently, we have demonstrated that a MEL metabolite N-acetyl-5-methoxykynuramine (AMK) promoted the formation of long-term object recognition memory more potently than MEL. Here, we examined the effects of 1 mg/kg MEL and AMK on both object location memory and spatial working memory. We also investigated the effects of the same dose of these drugs on relative phosphorylation/activation levels of memory-related proteins in the hippocampus (HP), the perirhinal cortex (PRC) and the medial prefrontal cortex (mPFC).Object location memory and spatial working memory were assessed using the object location task and the Y-maze spontaneous alternation task, respectively. Relative phosphorylation/activation levels of memory-related proteins were assessed using western blot analysis.AMK, as well as MEL, enhanced object location memory and spatial working memory. AMK increased the phosphorylation of cAMP-response element-binding protein (CREB) in both the HP and the mPFC 2 h after the treatment. AMK also increased the phosphorylation of extracellular signal-regulated kinases (ERKs) but decreased that of Ca2+/calmodulin-dependent protein kinases II (CaMKIIs) in the PRC and the mPFC 30 min after the treatment. MEL increased CREB phosphorylation in the HP 2 h after the treatment, whereas no detectable changes in the other proteins examined were observed.These results suggested the possibility that AMK exerts stronger memory-enhancing effects than MEL by more remarkably altering the activation of memory-related proteins such as ERKs, CaMKIIs and CREB in broader brain regions, including the HP, mPFC and PRC, compared to MEL.