Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice

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• 作者：Mitsugu Yoneda^a ; ¹ ; ^{yoneda@mhs.mp.kanazawa-u.ac.jp} ; Naotoshi Sugimoto^b ; ^c ; ^d ; ¹ ; ^{ns@med.kanazawa-u.ac.jp} ; Masanori Katakura^d ; ^e ; ^{mkatakur@josai.ac.jp} ; Kentaro Matsuzaki^d ; ^{matuzaki@med.shimane-u.ac.jp} ; Hayate Tanigami^a ; ^{t.hayate.0807@gmail.com} ; Akihiro Yachie^c ; ^{yachie@staff.kanazawa-u.ac.jp} ; Takako Ohno-Shosaku^a ; ^{shosaku@med.kanazawa-u.ac.jp} ; Osamu Shido^d ; ^{o-shido@med.shimane-u.ac.jp}
• 关键词：cAMP ; Phosphodiesterase ; Motor learning ; VASP phosphorylation ; BDNF ; CREB phosphorylation
• 刊名：The Journal of Nutritional Biochemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：39
• 期：Complete
• 页码：110-116
• 全文大小：545 K
• 卷排序：39

文摘

Theobromine, which is a caffeine derivative, is the primary methylxanthine produced by Theobroma cacao. Theobromine works as a phosphodiesterase (PDE) inhibitor to increase intracellular cyclic adenosine monophosphate (cAMP). cAMP activates the cAMP-response element-binding protein (CREB), which is involved in a large variety of brain processes, including the induction of the brain-derived neurotrophic factor (BDNF). BDNF supports cell survival and neuronal functions, including learning and memory. Thus, cAMP/CREB/BDNF pathways play an important role in learning and memory. Here, we investigated whether orally administered theobromine could act as a PDE inhibitor centrally and affect cAMP/CREB/BDNF pathways and learning behavior in mice. The mice were divided into two groups. The control group (CN) was fed a normal diet, whereas the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 30 days. We measured the levels of theobromine, phosphorylated vasodilator-stimulated phosphoprotein (p-VASP), phosphorylated CREB (p-CREB), and BDNF in the brain. p-VASP was used as an index of cAMP increases. Moreover, we analyzed the performance of the mice on a three-lever motor learning task. Theobromine was detectable in the brains of TB mice. The brain levels of p-VASP, p-CREB, and BDNF were higher in the TB mice compared with those in the CN mice. In addition, the TB mice performed better on the three-lever task than the CN mice did. These results strongly suggested that orally administered theobromine acted as a PDE inhibitor in the brain, and it augmented the cAMP/CREB/BDNF pathways and motor learning in mice.