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J Nutr Biochem. 2017 Jan;39:110-116. doi: 10.1016/j.jnutbio.2016.10.002. Epub 2016 Oct 8.

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

Author information

1
Impairment Study, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Takara-machi, Kanazawa, 920-0942, Japan. Electronic address: yoneda@mhs.mp.kanazawa-u.ac.jp.
2
Department of Physiology, Graduate School of Medical Sciences, Kanazawa University, 13-1 Takara-machi, Kanazawa, 920-8640, Japan; Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan; Department of Environmental Physiology, School of Medicine, Shimane University, 89-1 Enya-machi, Izumo, 693-8501, Japan. Electronic address: ns@med.kanazawa-u.ac.jp.
3
Department of Environmental Physiology, School of Medicine, Shimane University, 89-1 Enya-machi, Izumo, 693-8501, Japan; Department of Nutritional Physiology, Faculty of Pharmaceutical Sciences, Josai University, 1-1 Keyakidai, Sakado, 350-0295, Japan. Electronic address: mkatakur@josai.ac.jp.
4
Department of Environmental Physiology, School of Medicine, Shimane University, 89-1 Enya-machi, Izumo, 693-8501, Japan. Electronic address: matuzaki@med.shimane-u.ac.jp.
5
Impairment Study, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Takara-machi, Kanazawa, 920-0942, Japan. Electronic address: t.hayate.0807@gmail.com.
6
Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan. Electronic address: yachie@staff.kanazawa-u.ac.jp.
7
Impairment Study, Graduate School of Medical Sciences, Kanazawa University, 5-11-80 Kodatsuno, Takara-machi, Kanazawa, 920-0942, Japan. Electronic address: shosaku@med.kanazawa-u.ac.jp.
8
Department of Environmental Physiology, School of Medicine, Shimane University, 89-1 Enya-machi, Izumo, 693-8501, Japan. Electronic address: o-shido@med.shimane-u.ac.jp.

Abstract

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.

KEYWORDS:

BDNF; CREB phosphorylation; Motor learning; Phosphodiesterase; VASP phosphorylation; cAMP

PMID:
27833051
DOI:
10.1016/j.jnutbio.2016.10.002
[Indexed for MEDLINE]

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