Sub-Chronic Consumption of Dark Chocolate Enhances Cognitive Function and Releases Nerve Growth Factors: A Parallel-Group Randomized Trial

Eri Sumiyoshi, Kentaro Matsuzaki, Naotoshi Sugimoto, Yoko Tanabe, Toshiko Hara, Masanori Katakura, Mayumi Miyamoto, Seiji Mishima, Osamu Shido, Eri Sumiyoshi, Kentaro Matsuzaki, Naotoshi Sugimoto, Yoko Tanabe, Toshiko Hara, Masanori Katakura, Mayumi Miyamoto, Seiji Mishima, Osamu Shido

Abstract

Previous research has shown that habitual chocolate intake is related to cognitive performance and that frequent chocolate consumption is significantly associated with improved memory. However, little is known about the effects of the subchronic consumption of dark chocolate (DC) on cognitive function and neurotrophins. Eighteen healthy young subjects (both sexes; 20-31 years old) were randomly divided into two groups: a DC intake group (n = 10) and a cacao-free white chocolate (WC) intake group (n = 8). The subjects then consumed chocolate daily for 30 days. Blood samples were taken to measure plasma levels of theobromine (a methylxanthine most often present in DC), nerve growth factor (NGF), and brain-derived neurotrophic factor, and to analyze hemodynamic parameters. Cognitive function was assessed using a modified Stroop color word test and digital cancellation test. Prefrontal cerebral blood flow was measured during the tests. DC consumption increased the NGF and theobromine levels in plasma, enhancing cognitive function performance in both tests. Interestingly, the DC-mediated enhancement of cognitive function was observed three weeks after the end of chocolate intake. WC consumption did not affect NGF and theobromine levels or cognitive performance. These results suggest that DC consumption has beneficial effects on human health by enhancing cognitive function.

Keywords: Stroop color word test; cognitive function; dark chocolate; digital cancellation test; nerve growth factor; subchronic effect; theobromine; young-adult.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Experiment schedules. Subjects took chocolate daily for 30 days (Chocolate-intake intervention). The subjects’ physical characteristics, cognitive function test, and prefrontal cerebral blood flow (PFCBF) were recorded pre-(Pre) and postintervention (Post) and at a follow-up (FU) visit, 3 weeks after the end of the intervention. Blood was sampled before chocolate intake (baseline), during the chocolate intake intervention (1, 2, 3, and 4 weeks), and 3 weeks after the end of the intervention (FU).
Figure 2
Figure 2
A timeline of cognitive function tests. PFCBF were measured during the cognitive function tests. Preparation, the experimental instruments were attached for subject; rest, 5 min resting time.
Figure 3
Figure 3
The effects of dark chocolate (DC) and white chocolate (WC) intake on performance in the modified SCWT. The number of correct answers in word tests in the modified SCWT at Pre, Post, and FU for the DC group ((A), left panel) and the WC group ((A), right panel). The number of correct answers in the color tests at Pre, Post, and FU for the DC group ((B), left panel) and the WC group ((B), right panel). Values are the means ± SEM. * Significant differences vs. Pre at p < 0.05.
Figure 4
Figure 4
The effects of dark chocolate (DC) and white chocolate (WC) intake on PFCBF during the cognitive function tests. Average of oxygenated hemoglobin (Oxy-Hb) during the modified SCWT in word tests at Pre, Post, and FU for the DC group ((A), upper panel) and WC group ((A), lower panel). Average of Oxy-Hb during the modified SCWT in color tests at Pre, Post, and FU for the DC group ((B), upper panel) and the WC group ((B), lower panel). Average of Oxy-Hb during the D-CAT at Pre, Post, and FU for the DC group ((C), upper panel) and the WC group ((C), lower panel). Variables are expressed as changes (∆) from the baseline at the rest period in each trial. Means ± SEM bars are presented every 5 s.
Figure 5
Figure 5
The effects of dark chocolate (DC) and white chocolate (WC) intake on neurotrophins in the plasma. The NGF concentrations in plasma at Pre, Post, and FU for the DC group ((A), left panel) and the WC group ((A), right panel). The BDNF concentrations in plasma at Pre, Post, and FU for the DC group ((B), left panel) and the WC group ((B), right panel). Values are the means ± SEM. ** Significant differences vs. Pre at p < 0.01.
Figure 6
Figure 6
Changes in theobromine and caffeine concentrations in plasma of the DC group during the experimental period, including follow-up. Values are the means ± SEM. *** Significant differences vs. baseline at p < 0.001.

References

    1. Messerli F.H. Chocolate consumption, cognitive function, and nobel laureates. N. Engl. J. Med. 2012;367:1562–1564. doi: 10.1056/NEJMon1211064.
    1. Grassi D., Desideri G., Ferri C. Protective effects of dark chocolate on endothelial function and diabetes. Curr. Opin. Clin. Nutr. Metab. Care. 2013;16:662–668. doi: 10.1097/MCO.0b013e3283659a51.
    1. Scapagnini G., Davinelli S., di Renzo L., de Lorenzo A., Olarte H.H., Micali G., Cicero A.F., Gonzalez S. Cocoa bioactive compounds: Significance and potential for the maintenance of skin health. Nutrients. 2014;6:3202–3213. doi: 10.3390/nu6083202.
    1. Davinelli S., Corbi G., Zarrelli A., Arisi M., Calzavara-Pinton P., Grassi D., de Vivo I., Scapagnini G. Short-term supplementation with flavanol-rich cocoa improves lipid profile, antioxidant status and positively influences the AA/EPA ratio in healthy subjects. J. Nutr. Biochem. 2018;61:33–39. doi: 10.1016/j.jnutbio.2018.07.011.
    1. Brickman A.M., Khan U.A., Provenzano F.A., Yeung L., Suzuki W., Schroeter H., Wall M., Sloan R.P., Small S.A. Enhancing dentate gyrus function with dietary flavanols improves cognition in older adults. Nat. Neurosci. 2014;17:1798–1803. doi: 10.1038/nn.3850.
    1. Jalil A.M., Ismail A. Polyphenols in cocoa and cocoa products: Is there a link between antioxidant properties and health? Molecules. 2008;13:2190–2219. doi: 10.3390/molecules13092190.
    1. Crichton G.E., Elias M.F., Alkerwi A. Chocolate intake is associated with better cognitive function: The Maine-Syracuse Longitudinal Study. Appetite. 2016;100:126–132. doi: 10.1016/j.appet.2016.02.010.
    1. Taubert D., Roesen R., Lehmann C., Jung N., Schomig E. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide—A randomized controlled trial. Jama. 2007;298:49–60. doi: 10.1001/jama.298.1.49.
    1. Buijsse B., Weikert C., Drogan D., Bergmann M., Boeing H. Chocolate consumption in relation to blood pressure and risk of cardiovascular disease in German adults. Eur. Heart J. 2010;31:1616–1623. doi: 10.1093/eurheartj/ehq068.
    1. Nehlig A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br. J. Clin. Pharmacol. 2013;75:716–727. doi: 10.1111/j.1365-2125.2012.04378.x.
    1. Katz D.L., Doughty K., Ali A. Cocoa and chocolate in human health and disease. Antioxid. Redox Signal. 2011;15:2779–2811. doi: 10.1089/ars.2010.3697.
    1. Martinez-Pinilla E., Onatibia-Astibia A., Franco R. The relevance of theobromine for the beneficial effects of cocoa consumption. Front. Pharmacol. 2015;6:30. doi: 10.3389/fphar.2015.00030.
    1. Sugimoto N., Miwa S., Hitomi Y., Nakamura H., Tsuchiya H., Yachie A. Theobromine, the primary methylxanthine found in Theobroma cacao, prevents malignant glioblastoma proliferation by negatively regulating phosphodiesterase-4, extracellular signal-regulated kinase, Akt/mammalian target of rapamycin kinase, and nuclear factor-kappa B. Nutr. Cancer Int. J. 2014;66:419–423. doi: 10.1080/01635581.2013.877497.
    1. Yoneda M., Sugimoto N., Katakura M., Matsuzaki K., Tanigami H., Yachie A., Ohno-Shosaku T., Shido O. Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice. J. Nutr. Biochem. 2017;39:110–116. doi: 10.1016/j.jnutbio.2016.10.002.
    1. Sugimoto N., Katakura M., Matsuzaki K., Sumiyoshi E., Yachie A., Shido O. Chronic administration of theobromine inhibits mTOR signal in rats. Basic Clin. Pharmacol. Toxicol. 2019;124:575–581. doi: 10.1111/bcpt.13175.
    1. Kandel E.R. The molecular biology of memory: cAMP, PKA, CRE, CREB-1, CREB-2, and CPEB. Mol. Brain. 2012;5:14. doi: 10.1186/1756-6606-5-14.
    1. Lee D. Global and local missions of cAMP signaling in neural plasticity, learning, and memory. Front. Pharmacol. 2015;6:161. doi: 10.3389/fphar.2015.00161.
    1. Li Y.F., Cheng Y.F., Huang Y., Conti M., Wilson S.P., O’Donnell J.M., Zhang H.T. Phosphodiesterase-4D knock-out and RNA interference-mediated knock-down enhance memory and increase hippocampal neurogenesis via increased cAMP signaling. J. Neurosci. 2011;31:172–183. doi: 10.1523/JNEUROSCI.5236-10.2011.
    1. Islam R., Matsuzaki K., Sumiyoshi E., Hossain M.E., Hashimoto M., Katakura M., Sugimoto N., Shido O. Theobromine improves working memory by activating the CaMKII/CREB/BDNF pathway in rats. Nutrients. 2019;11:888. doi: 10.3390/nu11040888.
    1. Afoakwa E.O. Chocolate Science and Technology. 2nd ed. Wiley-Blackwell; Hoboken, NJ, USA: 2016. Chapter 2: World cocoa production, processing and chocolate consumption pattern; pp. 17–48.
    1. Fox M., Meyer-Gerspach A.C., Wendebourg M.J., Gruber M., Heinrich H., Sauter M., Woelnerhanssen B., Koeberle D., Juengling F. Effect of cocoa on the brain and gut in healthy subjects: A randomised controlled trial. Br. J. Nutr. 2019;121:654–661. doi: 10.1017/S0007114518003689.
    1. Pruijm M., Hofmann L., Charollais-Thoenig J., Forni V., Maillard M., Coristine A., Stuber M., Burnier M., Vogt B. Effect of dark chocolate on renal tissue oxygenation as measured by BOLD-MRI in healthy volunteers. Clin. Nephrol. 2013;80:211–217. doi: 10.5414/CN107897.
    1. Grassi D., Lippi C., Necozione S., Desideri G., Ferri C. Short-term administration of dark chocolate is followed by a significant increase in insulin sensitivity and a decrease in blood pressure in healthy persons. Am. J. Clin. Nutr. 2005;81:611–614. doi: 10.1093/ajcn/81.3.611.
    1. Gottumukkala R.V., Nadimpalli N., Sukala K., Subbaraju G.V. Determination of Catechin and Epicatechin content in chocolates by high-performance liquid chromatography. Int. Sch. Res. Not. 2014;2014:628196. doi: 10.1155/2014/628196.
    1. Pereira T., Bergqvist J., Vieira C., Sveälv B.G., Castanheira J., Conde J. Randomized study of the effects of cocoa-rich chocolate on the ventricle-arterial coupling and vascular function of young, healthy adults. Nutrition. 2019;63–64:175–183. doi: 10.1016/j.nut.2019.02.017.
    1. Alanon M.E., Castle S.M., Siswanto P.J., Cifuentes-Gomez T., Spencer J.P.E. Assessment of flavanol stereoisomers and caffeine and theobromine content in commercial chocolates. Food Chem. 2016;208:177–184. doi: 10.1016/j.foodchem.2016.03.116.
    1. Stroop J.R. Studies of interference in serial verbal reactions. J. Exp. Psychol. 1935;18:643–662. doi: 10.1037/h0054651.
    1. Hatta T., Yoshizaki K., Ito Y., Mase M., Kabasawa H. Reliability and validity of the digit cancellation test, a brief screen of attention. Psychologia. 2012;55:246–256. doi: 10.2117/psysoc.2012.246.
    1. Miyamoto M., Matsuzaki K., Katakura M., Hara T., Tanabe Y., Shido O. Oral intake of encapsulated dried ginger root powder hardly affects human thermoregulatory function, but appears to facilitate fat utilization. Int. J. Biometeorol. 2015;59:1461–1474. doi: 10.1007/s00484-015-0957-2.
    1. Massee L.A., Ried K., Pase M., Travica N., Yoganathan J., Scholey A., Macpherson H., Kennedy G., Sali A., Pipingas A. The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: A randomized, controlled trial. Front. Pharmacol. 2015;6:93. doi: 10.3389/fphar.2015.00093.
    1. Smit H.J., Gaffan E.A., Rogers P.J. Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology. 2004;176:412–419. doi: 10.1007/s00213-004-1898-3.
    1. Faridi Z., Njike V.Y., Dutta S., Ali A., Katz D.L. Acute dark chocolate and cocoa ingestion and endothelial function: A randomized controlled crossover trial. Am. J. Clin. Nutr. 2008;88:58–63. doi: 10.1093/ajcn/88.1.58.
    1. Mumford G.K., Benowitz N.L., Evans S.M., Kaminski B.J., Preston K.L., Sannerud C.A., Silverman K., Griffiths R.R. Absorption rate of methylxanthines following capsules, cola and chocolate. Eur. J. Clin. Pharmacol. 1996;51:319–325. doi: 10.1007/s002280050205.
    1. El Mohsen M.M.A., Kuhnle G., Rechner A.R., Schroeter H., Rose S., Jenner P., Rice-Evans C.A. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic. Biol. Med. 2002;33:1693–1702. doi: 10.1016/S0891-5849(02)01137-1.
    1. Steiner J.P., Nath A. Neurotrophin strategies for neuroprotection: Are they sufficient? J. Neuroimmune Pharmacol. 2014;9:182–194. doi: 10.1007/s11481-014-9533-5.
    1. Keefe K.M., Sheikh I.S., Smith G.M. Targeting neurotrophins to specific populations of neurons: NGF, BDNF, and NT-3 and their relevance for treatment of spinal cord injury. Int. J. Mol. Sci. 2017;18:548. doi: 10.3390/ijms18030548.
    1. Kowianski P., Lietzau G., Czuba E., Waskow M., Steliga A., Morys J. BDNF: A key factor with multipotent impact on brain signaling and synaptic plasticity. Cell. Mol. Neurobiol. 2018;38:579–593. doi: 10.1007/s10571-017-0510-4.
    1. Lim S., Moon M., Oh H., Kim H.G., Kim S.Y., Oh M.S. Ginger improves cognitive function via NGF-induced ERK/CREB activation in the hippocampus of the mouse. J. Nutr. Biochem. 2014;25:1058–1065. doi: 10.1016/j.jnutbio.2014.05.009.
    1. Lu B., Nagappan G., Lu Y. Neurotrophic Factors. Springer; Berlin/Heidelberg, Germany: 2014. BDNF and synaptic plasticity, cognitive function, and dysfunction; pp. 223–250.
    1. Francis S.T., Head K., Morris P.G., Macdonald I.A. The effect of flavanol-rich cocoa on the fMRI response to a cognitive task in healthy young people. J. Cardiovasc. Pharmacol. 2006;47:S215–S220. doi: 10.1097/00005344-200606001-00018.
    1. Sorond F.A., Lipsitz L.A., Hollenberg N.K., Fisher N.D. Cerebral blood flow response to flavanol-rich cocoa in healthy elderly humans. Neuropsychiatr. Dis. Treat. 2008;4:433–440.
    1. Monahan K.D., Feehan R.P., Kunselman A.R., Preston A.G., Miller D.L., Lott M.E.J. Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults. J. Appl. Physiol. 2011;111:1568–1574. doi: 10.1152/japplphysiol.00865.2011.
    1. Njike V.Y., Faridi Z., Shuval K., Dutta S., Kay C.D., West S.G., Kris-Etherton P.M., Katz D.L. Effects of sugar-sweetened and sugar-free cocoa on endothelial function in overweight adults. Int. J. Cardiol. 2011;149:83–88. doi: 10.1016/j.ijcard.2009.12.010.
    1. Pomportes L., Brisswalter J., Casini L., Hays A., Davranche K. Cognitive performance enhancement induced by caffeine, carbohydrate and guarana mouth rinsing during submaximal exercise. Nutrients. 2017;9:589. doi: 10.3390/nu9060589.
    1. Loprinzi P.D., Lovorn A. Exercise and cognitive function. J. Clin. Med. 2019;8:1707. doi: 10.3390/jcm8101707.

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