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

<jats:sec><jats:title>Objectives</jats:title><jats:p>Melatonin (MEL) has been reported to enhance cognitive performance. Recently, we have demonstrated that a MEL metabolite<jats:italic toggle="yes">N</jats:italic>-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).</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>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 Ca<jats:sup>2+</jats:sup>/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.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>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.</jats:p></jats:sec>