Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice.
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.
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.
Mitsugu
M
Yoneda
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.
Naotoshi
N
Sugimoto
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.
Masanori
M
Katakura
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.
Kentaro
K
Matsuzaki
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.
Hayate
H
Tanigami
Pediatrics, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, 920-8640, Japan. Electronic address: yachie@staff.kanazawa-u.ac.jp.
Akihiro
A
Yachie
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.
Takako
T
Ohno-Shosaku
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.
Osamu
O
Shido
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D002099:Cacao / Q000737:chemistry; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D007858:Learning; D008297:Male; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D010936:Plant Extracts / Q000494:pharmacology; D013805:Theobromine / Q000097:blood / Q000494:pharmacology*; D015854:Up-Regulation; D000098662:Vasodilator-Stimulated Phosphoprotein
D001786:Blood Glucose; D019208:Brain-Derived Neurotrophic Factor; D015815:Cell Adhesion Molecules; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D008840:Microfilament Proteins; D010726:Phosphodiesterase Inhibitors; D010750:Phosphoproteins; D010936:Plant Extracts; D000098662:Vasodilator-Stimulated Phosphoprotein; C579455:BDNF protein, human; D000242:Cyclic AMP; D013805:Theobromine
BDNF; CREB phosphorylation; Motor learning; Phosphodiesterase; VASP phosphorylation; cAMP