Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats.

Rafiad Islam,Naotoshi Sugimoto,Kentaro Matsuzaki,Md Emon Hossain,Michio Hashimoto,Eri Sumiyoshi,Osamu Shido,Masanori Katakura

doi:10.3390/nu11040888

Abstract

Theobromine (TB) is a primary methylxanthine found in cacao beans. cAMP-response element-binding protein (CREB) is a transcription factor, which is involved in different brain processes that bring about cellular changes in response to discrete sets of instructions, including the induction of brain-derived neurotropic factor (BDNF). Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been strongly implicated in the memory formation of different species as a key regulator of gene expression. Here we investigated whether TB acts on the CaMKII/CREB/BDNF pathway in a way that might improve the cognitive and learning function in rats. Male Wistar rats (5 weeks old) were divided into two groups. For 73 days, the control rats (CN rats) were fed a normal diet, while the TB-fed rats (TB rats) received the same food, but with a 0.05% TB supplement. To assess the effects of TB on cognitive and learning ability in rats: The radial arm maze task, novel object recognition test, and Y-maze test were used. Then, the brain was removed and the medial prefrontal cortex (mPFC) was isolated for Western Blot, real-time PCR and enzyme-linked immunosorbent assay. Phosphorylated CaMKII (p-CaMKII), phosphorylated CREB (p-CREB), and BDNF level in the mPFC were measured. In all the behavior tests, working memory seemed to be improved by TB ingestion. In addition, p-CaMKII and p-CREB levels were significantly elevated in the mPFC of TB rats in comparison to those of CN rats. We also found that cortical BDNF protein and mRNA levels in TB rats were significantly greater than those in CN rats. These results suggest that orally supplemented TB upregulates the CaMKII/CREB/BDNF pathway in the mPFC, which may then improve working memory in rats.

Highlights

Coffee, cocoa, and chocolate are among the most frequently consumed substances in the world [1]
The results of our present study demonstrated that the oral administration of TB influenced the signaling pathway in present the medial prefrontal cortex (mPFC), including those for and brain-derived neurotrophic factor (BDNF), and concurrently
This study demonstrated that the oral administration of TB for 73 days resulted in the upregulation of p-calmodulin-dependent protein kinase II (CaMKII) and p-cAMP-response element-binding protein (CREB) in the mPFC, and found both BDNF mRNA expression level, as well as protein level upregulation in the mPFC of TB-fed rats (TB rats)

Summary

Introduction

Cocoa, and chocolate are among the most frequently consumed substances in the world [1]. Coffee has various beneficial effects on human health, as it appears to be cardio-protective, Nutrients 2019, 11, 888; doi:10.3390/nu11040888 www.mdpi.com/journal/nutrients. Nutrients 2019, 11, 888 neuroprotective, hepatoprotective, and nephroprotective. There has been a notable interest in the neuroprotective effects of flavonoids, with evidence emerging that they may lead to improvements in memory and learning by improving neuronal functioning, while promoting neuronal protection and regeneration [3]. A very popular food worldwide, contains many flavonoids, which have pleotropic effects in cognition and neuroprotection [4,5]. Theobromine (TB) is a primary methylxanthine found in products made from cacao beans, which generally contain approximately

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Discussion

Conclusion