PMID- 31010016 OWN - NLM STAT- MEDLINE DCOM- 20191104 LR - 20200225 IS - 2072-6643 (Electronic) IS - 2072-6643 (Linking) VI - 11 IP - 4 DP - 2019 Apr 20 TI - Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats. LID - 10.3390/nu11040888 [doi] LID - 888 AB - 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). Ca(2+)/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. FAU - Islam, Rafiad AU - Islam R AUID- ORCID: 0000-0001-5039-6240 AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. rafiad@med.shimane-u.ac.jp. AD - Department of Biotechnology and Genetic Engineering, Mawlana Bhashani Science and Technology University, Tangail 1902, Bangladesh. rafiad@med.shimane-u.ac.jp. FAU - Matsuzaki, Kentaro AU - Matsuzaki K AUID- ORCID: 0000-0002-5942-8840 AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. matuzaki@med.shimane-u.ac.jp. FAU - Sumiyoshi, Eri AU - Sumiyoshi E AUID- ORCID: 0000-0003-4871-3934 AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. erisumi@med.shimane-u.ac.jp. FAU - Hossain, Md Emon AU - Hossain ME AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. emon@uab.edu. AD - Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham AL 35294, USA. emon@uab.edu. FAU - Hashimoto, Michio AU - Hashimoto M AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. michio1@med.shimane-u.ac.jp. FAU - Katakura, Masanori AU - Katakura M AUID- ORCID: 0000-0002-2237-9651 AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. mkatakur@josai.ac.jp. AD - Department of Nutritional Physiology, Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, Japan. mkatakur@josai.ac.jp. FAU - Sugimoto, Naotoshi AU - Sugimoto N AUID- ORCID: 0000-0003-1995-5002 AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. ns@med.kanazawa-u.ac.jp. AD - Department of Physiology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-8640, Japan. ns@med.kanazawa-u.ac.jp. FAU - Shido, Osamu AU - Shido O AD - Department of Environmental Physiology, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan. o-shido@med.shimane-u.ac.jp. LA - eng GR - 17H01963 and 25282021/Ministry of Education, Culture, Sports, Science and Technology/ PT - Journal Article DEP - 20190420 PL - Switzerland TA - Nutrients JT - Nutrients JID - 101521595 RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Plant Extracts) RN - 0 (RNA, Messenger) RN - EC 2.7.11.17 (Calcium-Calmodulin-Dependent Protein Kinase Type 2) RN - OBD445WZ5P (Theobromine) SB - IM MH - Animals MH - Brain/*drug effects/metabolism MH - Brain-Derived Neurotrophic Factor/*metabolism MH - Cacao/*chemistry MH - Calcium-Calmodulin-Dependent Protein Kinase Type 2/*metabolism MH - Cyclic AMP Response Element-Binding Protein/*metabolism MH - Dietary Supplements MH - Male MH - Maze Learning/drug effects MH - Memory, Short-Term/*drug effects/physiology MH - Phosphorylation MH - Phytotherapy MH - Plant Extracts/pharmacology MH - RNA, Messenger/metabolism MH - Rats, Wistar MH - Signal Transduction MH - Theobromine/*pharmacology PMC - PMC6520707 OTO - NOTNLM OT - BDNF OT - CREB OT - CaMKII OT - behavior OT - cacao OT - theobromine OT - working memory COIS- The authors declare no conflict of interest. EDAT- 2019/04/24 06:00 MHDA- 2019/11/05 06:00 PMCR- 2019/04/01 CRDT- 2019/04/24 06:00 PHST- 2019/02/22 00:00 [received] PHST- 2019/04/05 00:00 [revised] PHST- 2019/04/17 00:00 [accepted] PHST- 2019/04/24 06:00 [entrez] PHST- 2019/04/24 06:00 [pubmed] PHST- 2019/11/05 06:00 [medline] PHST- 2019/04/01 00:00 [pmc-release] AID - nu11040888 [pii] AID - nutrients-11-00888 [pii] AID - 10.3390/nu11040888 [doi] PST - epublish SO - Nutrients. 2019 Apr 20;11(4):888. doi: 10.3390/nu11040888.