Abstract
Nutritional qualities of cocoa have been acknowledged by several authors; a particular focus has been placed on its high content of flavanols, known for their excellent antioxidant properties and subsequent protective effect on cardio- and cerebrovascular systems as well as for neuromodulatory and neuroprotective actions. Other active components of cocoa are methylxanthines (caffeine and theobromine). Whereas the effects of caffeine are extensively researched, the same is not the case for theobromine; this review summarizes evidence on the effect of theobromine on cognitive functions. Considering animal studies, it can be asserted that acute exposition to theobromine has a reduced and delayed nootropic effect with respect to caffeine, whereas both animal and human studies suggested a potential neuroprotective action of long-term assumption of theobromine through a reduction of Aβ amyloid pathology, which is commonly observed in Alzheimer’s disease patients’ brains. Hence, the conceivable action of theobromine alone and associated with caffeine or other cocoa constituents on cognitive modulation is yet underexplored and future studies are needed to shed light on this promising molecule.
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References
Baggott MJ, Childs E, Hart AB, de Bruin E, Palmer AA, Wilkinson JE, de Wit H (2013) Psychopharmacology of theobromine in healthy volunteers. Psychopharmacology 228:109–118. https://doi.org/10.1007/s00213-013-3021-0
Bruinsma K, Taren DL (1999) Chocolate: food or drug? J Am Diet Assoc 99:1249–1256. https://doi.org/10.1016/S0002-8223(99)00307-7
Brunk SF, Ferguson RK, Toubes DB et al (1973) A teaching format in clinical pharmacology. Comparison of two xanthines and a placebo. J Clin Pharmacol New Drugs 13:121–126
Carney JM (1982) Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats. Br J Pharmacol 75:451–454
Carney JM, Cao W, Logan L et al (1986) Differential antagonism of the behavioral depressant and hypothermic effects of 5′-(N-ethylcarboxamide) adenosine by theobromine. Pharmacol Biochem Behav 25:769–773
Chen J-F, Chern Y (2011) Impacts of methylxanthines and adenosine receptors on neurodegeneration: human and experimental studies. Handb Exp Pharmacol:267–310. https://doi.org/10.1007/978-3-642-13443-2_10
Coleman WF (2004) Chocolate: theobromine and caffeine. J Chem Educ 81:1232. https://doi.org/10.1021/ed081p1232
Crichton GE, Elias MF, ‘a AA (2016) Chocolate intake is associated with better cognitive function: the Maine-Syracuse Longitudinal Study. Appetite 100:126–132. https://doi.org/10.1016/j.appet.2016.02.010
Dall’Igna OP, Fett P, Gomes MW et al (2007) Caffeine and adenosine A(2a) receptor antagonists prevent beta-amyloid (25-35)-induced cognitive deficits in mice. Exp Neurol 203:241–245. https://doi.org/10.1016/j.expneurol.2006.08.008
del Rosario Brunetto M, Gutiérrez L, Delgado Y et al (2007) Determination of theobromine, theophylline and caffeine in cocoa samples by a high-performance liquid chromatographic method with on-line sample cleanup in a switching-column system. Food Chem 100:459–467. https://doi.org/10.1016/j.foodchem.2005.10.007
Dorfman LJ, Jarvik ME (1970) Comparative stimulant and diuretic actions of caffeine and theobromine in man. Clin Pharmacol Ther 11:869–872
Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55. https://doi.org/10.1146/annurev.neuro.24.1.31
Essayan DM (2001) Cyclic nucleotide phosphodiesterases. J Allergy Clin Immunol 108:671–680. https://doi.org/10.1067/mai.2001.119555
Fernández-Fernández L, Esteban G, Giralt M, Valente T, Bolea I, Solé M, Sun P, Benítez S, Morelló JR, Reguant J, Ramírez B, Hidalgo J, Unzeta M (2015) Catecholaminergic and cholinergic systems of mouse brain are modulated by LMN diet, rich in theobromine, polyphenols and polyunsaturated fatty acids. Food Funct 6:1251–1260. https://doi.org/10.1039/c5fo00052a
Fredholm BB (ed) (2011) Methylxanthines. Springer Verlag, Berlin
Geraets L, Moonen HJJ, Wouters EFM, Bast A, Hageman GJ (2006) Caffeine metabolites are inhibitors of the nuclear enzyme poly(ADP-ribose)polymerase-1 at physiological concentrations. Biochem Pharmacol 72:902–910. https://doi.org/10.1016/j.bcp.2006.06.023
He R, Xie G, Yao X-S, Kurihara H (2009) Effect of cocoa tea ( Camellia ptilophylla ) co-administrated with green tea on ambulatory behaviors. Biosci Biotechnol Biochem 73:957–960. https://doi.org/10.1271/bbb.80815
Hetherington MM (2001) Food cravings and addiction. Leatherhead food RA publ., Leatherhead
Ishay JS, Paniry VA (1979) Effects of caffeine and various xanthines on hornets and bees. Psychopharmacology 65:299–309
Judelson DA, Preston AG, Miller DL, Muñoz CX, Kellogg MD, Lieberman HR (2013) Effects of theobromine and caffeine on mood and vigilance. J Clin Psychopharmacol 33:499–506. https://doi.org/10.1097/JCP.0b013e3182905d24
Kovács Z, Juhász G, Palkovits M et al (2011) Area, age and gender dependence of the nucleoside system in the brain: a review of current literature. Curr Top Med Chem 11:1012–1033
Koyama Y, Tomoda Y, Kato M, Ashihara H (2003) Metabolism of purine bases, nucleosides and alkaloids in theobromine-forming Theobroma cacao leaves. Plant Physiol Biochem 41:977–984. https://doi.org/10.1016/j.plaphy.2003.07.002
Kuribara H, Asahi T, Tadokoro S (1992) Behavioral evaluation of psycho-pharmacological and psychotoxic actions of methylxanthines by ambulatory activity and discrete avoidance in mice. J Toxicol Sci 17:81–90
Lamuela-Raventos RM (2005) Review: health effects of cocoa flavonoids. Food Sci Technol Int 11:159–176. https://doi.org/10.1177/1082013205054498
Maleyki MJA, Ismail A (2010) Antioxidant properties of cocoa powder. J Food Biochem 34:111–128. https://doi.org/10.1111/j.1745-4514.2009.00268.x
Marriott BM, Institute of Medicine (U.S.), Committee on Military Nutrition Research (1994) Food components to enhance performance: an evaluation of potential performance-enhancing food components for operational rations. National Academy Press, Washington, D.C.
Martínez-Pinilla E, Oñatibia-Astibia A, Franco R (2015) The relevance of theobromine for the beneficial effects of cocoa consumption. Front Pharmacol 6:30. https://doi.org/10.3389/fphar.2015.00030
Mendiola-Precoma J, Padilla K, Rodríguez-Cruz A, Berumen LC, Miledi R, García-Alcocer G (2017) Theobromine-induced changes in A1 purinergic receptor gene expression and distribution in a rat brain Alzheimer’s disease model. J Alzheimers Dis JAD 55:1273–1283. https://doi.org/10.3233/JAD-160569
Mitchell ES, Slettenaar M, vd Meer N, Transler C, Jans L, Quadt F, Berry M (2011) Differential contributions of theobromine and caffeine on mood, psychomotor performance and blood pressure. Physiol Behav 104:816–822. https://doi.org/10.1016/j.physbeh.2011.07.027
Mumford GK, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR (1994) Discriminative stimulus and subjective effects of theobromine and caffeine in humans. Psychopharmacology 115:1–8
Mumford GK, Benowitz NL, Evans SM, Kaminski BJ, Preston KL, Sannerud CA, Silverman K, Griffiths RR (1996) Absorption rate of methylxanthines following capsules, cola and chocolate. Eur J Clin Pharmacol 51:319–325
Panza F, Solfrizzi V, Barulli MR, Bonfiglio C, Guerra V, Osella A, Seripa D, Sabbà C, Pilotto A, Logroscino G (2015) Coffee, tea, and caffeine consumption and prevention of late-life cognitive decline and dementia: a systematic review. J Nutr Health Aging 19:313–328. https://doi.org/10.1007/s12603-014-0563-8
Penetar D, McCann U, Thorne D, Kamimori G, Galinski C, Sing H, Thomas M, Belenky G (1993) Caffeine reversal of sleep deprivation effects on alertness and mood. Psychopharmacology 112:359–365
Petersen RC, Caracciolo B, Brayne C, Gauthier S, Jelic V, Fratiglioni L (2014) Mild cognitive impairment: a concept in evolution. J Intern Med 275:214–228. https://doi.org/10.1111/joim.12190
Peters-Golden M, Canetti C, Mancuso P, Coffey MJ (2005) Leukotrienes: underappreciated mediators of innate immune responses. J Immunol 174:589–594
Petyaev IM, Bashmakov YK (2016) Cocobiota: implications for human health. J Nutr Metab 2016:7906927. https://doi.org/10.1155/2016/7906927
Pittenauer E, Allmaier G (2009) The renaissance of high-energy CID for structural elucidation of complex lipids: MALDI-TOF/RTOF-MS of alkali cationized triacylglycerols. J Am Soc Mass Spectrom 20:1037–1047. https://doi.org/10.1016/j.jasms.2009.01.009
Rabin LA, Smart CM, Amariglio RE (2017) Subjective cognitive decline in preclinical Alzheimer’s disease. Annu Rev Clin Psychol 13:369–396. https://doi.org/10.1146/annurev-clinpsy-032816-045136
Rahman A (2009) The role of adenosine in Alzheimers disease. Curr Neuropharmacol 7:207–216. https://doi.org/10.2174/157015909789152119
Romero-Cortes T, Salgado-Cervantes MA, García-Alamilla P, García-Alvarado MA, del C Rodríguez-Jimenes G, Hidalgo-Morales M, Robles-Olvera V (2013) Relationship between fermentation index and other biochemical changes evaluated during the fermentation of Mexican cocoa (Theobroma cacao) beans. J Sci Food Agric 93:2596–2604. https://doi.org/10.1002/jsfa.6088
Rusconi M, Conti A (2010) Theobroma cacao L., the food of the gods: a scientific approach beyond myths and claims. Pharmacol Res 61:5–13. https://doi.org/10.1016/j.phrs.2009.08.008
Schindler CW, Karcz-Kubicha M, Thorndike EB, Müller CE, Tella SR, Ferré S, Goldberg SR (2005) Role of central and peripheral adenosine receptors in the cardiovascular responses to intraperitoneal injections of adenosine A 1 and A 2A subtype receptor agonists. Br J Pharmacol 144:642–650. https://doi.org/10.1038/sj.bjp.0706043
Sheth S, Brito R, Mukherjea D, Rybak L, Ramkumar V (2014) Adenosine receptors: expression, function and regulation. Int J Mol Sci 15:2024–2052. https://doi.org/10.3390/ijms15022024
Shi D, Daly JW (1999) Chronic effects of xanthines on levels of central receptors in mice. Cell Mol Neurobiol 19:719–732
Simons FE, Becker AB, Simons KJ, Gillespie CA (1985) The bronchodilator effect and pharmacokinetics of theobromine in young patients with asthma. J Allergy Clin Immunol 76:703–707
Smit HJ (2011) Theobromine and the pharmacology of cocoa. Handb Exp Pharmacol:201–234. https://doi.org/10.1007/978-3-642-13443-2_7
Smit HJ, Blackburn RJ (2005) Reinforcing effects of caffeine and theobromine as found in chocolate. Psychopharmacology 181:101–106. https://doi.org/10.1007/s00213-005-2209-3
Smit HJ, Gaffan EA, Rogers PJ (2004) Methylxanthines are the psycho-pharmacologically active constituents of chocolate. Psychopharmacology 176:412–419. https://doi.org/10.1007/s00213-004-1898-3
Snyder SH, Katims JJ, Annau Z, Bruns RF, Daly JW (1981) Adenosine receptors and behavioral actions of methylxanthines. Proc Natl Acad Sci U S A 78:3260–3264
Sprügel W, Mitznegg P, Heim F (1977) The influence of caffeine and theobromine on locomotive activity and the brain cGMP/cAMP ratio in white mice. Biochem Pharmacol 26:1723–1724
Sugimoto N, Miwa S, Hitomi Y, Nakamura H, Tsuchiya H, Yachie A (2014) 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 66:419–423. https://doi.org/10.1080/01635581.2013.877497
Svenningsson P, Nomikos GG, Fredholm BB (1999) The stimulatory action and the development of tolerance to caffeine is associated with alterations in gene expression in specific brain regions. J Neurosci 19:4011–4022
Sweitzer S, De Leo J (2011) Propentofylline: glial modulation, neuroprotection, and alleviation of chronic pain. In: Methylxanthines. Springer Berlin Heidelberg, Berlin, pp 235–250
Travassos M, Santana I, Baldeiras I, Tsolaki M, Gkatzima O, Sermin G, Yener GG, Simonsen A, Hasselbalch SG, Kapaki E, Mara B, Cunha RA, Agostinho P, Blennow K, Zetterberg H, Mendes VM, Manadas B, de Mendon A (2015) Does caffeine consumption modify cerebrospinal fluid amyloid-β levels in patients with Alzheimer’s disease? J Alzheimers Dis JAD 47:1069–1078. https://doi.org/10.3233/JAD-150374
Usmani OS, Belvisi MG, Patel HJ, Crispino N, Birrell MA, Korbonits M, Korbonits D, Barnes PJ (2005) Theobromine inhibits sensory nerve activation and cough. FASEB J Off Publ Fed Am Soc Exp Biol 19:231–233. https://doi.org/10.1096/fj.04-1990fje
Valente T, Hidalgo J, Bolea I, Ramirez B, Anglés N, Reguant J, Morelló JR, Gutiérrez C, Boada M, Unzeta M (2009) A diet enriched in polyphenols and polyunsaturated fatty acids, LMN diet, induces neurogenesis in the subventricular zone and hippocampus of adult mouse brain. J Alzheimers Dis JAD 18:849–865. https://doi.org/10.3233/JAD-2009-1188
van den Bogaard B, Draijer R, Westerhof BE, van den Meiracker AH, van Montfrans GA, van den Born BJH (2010) Effects on peripheral and central blood pressure of cocoa with natural or high-dose theobromine: a randomized, double-blind crossover trial. Hypertension 56:839–846. https://doi.org/10.1161/HYPERTENSIONAHA.110.158139
Vauzour D (2014) Effect of flavonoids on learning, memory and neurocognitive performance: relevance and potential implications for Alzheimer’s disease pathophysiology: flavonoids and memory. J Sci Food Agric 94:1042–1056. https://doi.org/10.1002/jsfa.6473
von Linné (Linneaus) (1741) C. Om chokladdryken
Watson RR, Preedy VR, Zibadi S (eds) (2013) Chocolate in health and nutrition. Humana Press/Springer Verlag, New York
Wolf LK (2013) Caffeine Jitters. Chem Eng News Arch 91:9–12. https://doi.org/10.1021/cen-09105-cover
Yoneda M, Sugimoto N, Katakura M, Matsuzaki K, Tanigami H, Yachie A, Ohno-Shosaku T, Shido O (2017) Theobromine up-regulates cerebral brain-derived neurotrophic factor and facilitates motor learning in mice. J Nutr Biochem 39:110–116. https://doi.org/10.1016/j.jnutbio.2016.10.002
Zak DL, Keeney PG (1976) Extraction and fractionation of cocoa proteins as applied to several varieties of cocoa beans. J Agric Food Chem 24:479–483
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Cova, I., Leta, V., Mariani, C. et al. Exploring cocoa properties: is theobromine a cognitive modulator?. Psychopharmacology 236, 561–572 (2019). https://doi.org/10.1007/s00213-019-5172-0
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DOI: https://doi.org/10.1007/s00213-019-5172-0