International Journal of Molecular Sciences Review Neuroprotective Effects of Coffee Bioactive Compounds: A Review Katarzyna Socała 1,* , Aleksandra Szopa 2 , Anna Serefko 2 , Ewa Poleszak 2 and Piotr Wla´z 1 1 Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, Akademicka 19, 20-033 Lublin, Poland; [email protected] 2 Laboratory of Preclinical Testing, Chair and Department of Applied and Social Pharmacy, Medical University of Lublin, Chod´zki1, 20-093 Lublin, Poland; [email protected] (A.S.); [email protected] (A.S.); [email protected] (E.P.) * Correspondence: [email protected] Abstract: Coffee is one of the most widely consumed beverages worldwide. It is usually identified as a stimulant because of a high content of caffeine. However, caffeine is not the only coffee bioactive component. The coffee beverage is in fact a mixture of a number of bioactive compounds such as polyphenols, especially chlorogenic acids (in green beans) and caffeic acid (in roasted coffee beans), alkaloids (caffeine and trigonelline), and the diterpenes (cafestol and kahweol). Extensive research shows that coffee consumption appears to have beneficial effects on human health. Regular coffee intake may protect from many chronic disorders, including cardiovascular disease, type 2 diabetes, obesity, and some types of cancer. Importantly, coffee consumption seems to be also correlated with a decreased risk of developing some neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, and dementia. Regular coffee intake may also reduce the risk of stroke. The mechanism underlying these effects is, however, still poorly understood. This review summarizes the current knowledge on the neuroprotective potential of the main bioactive coffee components, i.e., caffeine, chlorogenic acid, caffeic acid, trigonelline, kahweol, and cafestol. Data from both in vitro and in vivo preclinical experiments, including their potential therapeutic applications, are reviewed and discussed. Epidemiological studies and clinical reports on this matter are also described. Moreover, potential molecular mechanism(s) by which coffee bioactive components may provide Citation: Socała, K.; Szopa, A.; neuroprotection are reviewed. Serefko, A.; Poleszak, E.; Wla´z, P. Neuroprotective Effects of Coffee Keywords: coffee consumption; caffeine; chlorogenic acid; caffeic acid; trigonelline; neuroprotection; Bioactive Compounds: A Review. Int. Alzheimer’s disease; Parkinson’s disease; stroke J. Mol. Sci. 2021, 22, 107. https://dx.doi. org/10.3390/ijms22010107 Received: 10 November 2020 Accepted: 22 December 2020 1. Introduction Published: 24 December 2020 The genus Coffea L. (family: Rubiaceae, subfamily: Ixoroideae, tribe: Coffeeae) includes at least 125 species which naturally occur in Tropical and East Africa, Tropical Asia, and Publisher’s Note: MDPI stays neu- Australia and also in the Comoros, Madagascar, and the Mascarenes [1]. Only three of tral with regard to jurisdictional claims these species are used in the commercial coffee production, i.e., Coffea arabica L. (Arabica in published maps and institutional coffee), Coffea canephora Pierre ex A. Froehner (Robusta coffee), and Coffea liberica Hiern affiliations. (Excelsa coffee) [2–6]. Coffee beans are obtained from the tart red fruit of the evergreen coffee tree. They are used primarily in the food industry but also in cosmetology and medicine. Nowadays, Copyright: © 2020 by the authors. Li- coffee is considered to be one of the most highly popular and widely consumed pharma- censee MDPI, Basel, Switzerland. This cologically active universal beverages [7,8], and its drinking has become a regular part article is an open access article distributed of daily life [9]. It is estimated that in 2019/2020 world coffee consumption amounted to under the terms and conditions of the about 10.1 million kg [10]. Most of all coffee is used due to its psychostimulating effect, Creative Commons Attribution (CC BY) taste and aroma as well as health-promoting properties [11]. license (https://creativecommons.org/ The health effects of coffee consumption have been investigated in numerous re- licenses/by/4.0/). search [12–19]. The outcomes from many of these studies showed the positive impact of Int. J. Mol. Sci. 2021, 22, 107. https://dx.doi.org/10.3390/ijms22010107 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 2 of 63 Int. J. Mol. Sci. 2021, 22, 107 2 of 64 The health effects of coffee consumption have been investigated in numerous re- search [12–19]. The outcomes from many of these studies showed the positive impact of coffee intakeintake onon various various aspects aspects of of health, health, e.g., e.g., coffee coffee possesses possesses anti-oxidant anti-oxidant (especially (especially the medium-roastedthe medium-roasted coffee) coffee) [20] and[20] anti-inflammatoryand anti-inflammatory properties properties [15] and [15] limits and the limits overall the riskoverall of strokerisk of andstroke coronary and coronary heart disease heart disease [21–23 ],[21 cancer–23], cancer [22,24 ,[22,24,25],25], mortality mortality associated asso- withciated cardiovascular with cardiovascular disease disease [22,26 ],[22,26], Parkinson’s Parkinson’s [22,27 [22,27,28],28] and Alzheimer’s and Alzheimer’s disease disease and otherand other neurodegenerative neurodegenerative disorders disorders [29, 30[29,30],], depression depression and an suicided suicide [31 ,[31,32],32], liver liver damage dam- particularlyage particularly in patients in patients at high at high risk forrisk liver for liver disease, disease, such assuch cirrhosis, as cirrhosis, hepatocellular hepatocellular carci- nomacarcinoma and hepaticand hepatic injury injury [22,23 [22,23,33],,33], and developingand developing type type 2 diabetes 2 diabetes [7,19 [7,19,22,23].,22,23]. However, How- excessiveever, excessive coffee coffee drinkers drinkers also experience also experience negative negative effects effects of its use,of its e.g., use, caffeine e.g., caffeine raises concentrationraises concentration of total of cholesterol total cholesterol and lowers and lowers high densityhigh density lipoprotein lipoprotein in serum in serum [34] and[34] causesand causes cardiovascular cardiovascular problems, problems, including including increased increased blood blood pressure, pressure, tachycardia, tachycardia, and arrhythmiaand arrhythmia [21,23 [21,23,24].,24]. Such multidirectionalmultidirectional effects effects of of coffee coffee on on the the human human health health and and body body are dueare due to the to factthe thatfact that it is ait complexis a complex mixture mixture of bioactive of bioactive ingredients ingredients and both and nutrientsboth nutrients and non-nutrients and non-nu- whichtrients actwhich together act together [35]. The [35]. composition The composition of these of these elements elements in coffee in coffee beans beans differs differs and dependsand depends on (1) on species (1) species of coffee; of coffee; (2) conditions(2) conditions of roasting of roasting of the of the coffee coffee beans, beans, including includ- temperature,ing temperature, time, time, and speedand speed of this of process; this proc (3)ess; coffee (3) brewingcoffee brewing conditions, conditions, i.e., the brewing i.e., the method,brewing coffee/watermethod, coffee/water ratio, temperature ratio, temperature of water, sizeof water, of coffee size grind, of coffee and grind, duration and of dura- this processtion of this [35 –process37]. The [35 most–37]. importantThe most important bioactive compoundsbioactive compounds in coffee thatin coffee might that serve might as physiologicallyserve as physiologically effective agentseffective include agents caffeine, include chlorogeniccaffeine, chlorogenic acids, cafestol acids, and cafestol kahweol, and trigonellinekahweol, trigonelline (Figure1), (Figure and melanoidins 1), and melanoid (Figureins2)[ (Figure17,38, 392) ].[17,38,39]. The detailed The detailed chemical chem- com- position and content of active, nutritional, and mineral substances in green and roasted ical composition and content of active, nutritional, and mineral substances in green and coffee beans and coffee beverage or brew are given in Tables1 and2, respectively. roasted coffee beans and coffee beverage or brew are given in Tables 1 and 2, respectively. FigureFigure 1.1. Structures ofof thethe mostmost importantimportant bioactivebioactive compoundscompounds inin coffee.coffee. ((A)) structuresstructures ofof keykey compoundscompounds notnot belongingbelonging toto chlorogenicchlorogenic acids,acids, ((BB)) generalgeneral structurestructure ofof chlorogenicchlorogenic acidsacids andand thethe mostmost importantimportant groupsgroups foundfound inin chlorogenicchlorogenic acidsacids fromfrom coffeecoffee beans,beans, ((CC)) structuresstructures ofof caffeoylquiniccaffeoylquinic acids acids found found in in coffee coffee beans. beans. Int. J. Mol. Sci. 2021, 22, 107 3 of 64 Int. J. Mol. Sci. 2020, 21, x FOR PEER REVIEW 3 of 63 Figure 2. ExamplesFigure of 2.theExamples structure ofof thecoffee structure melanoidins of coffee [38,39]. melanoidins [38,39]. 2. Bioavailability and Pharmacokinetics of Coffee Bioactive Compounds 2. Bioavailability and Pharmacokinetics of Coffee Bioactive Compounds 2.1. Caffeine 2.1. Caffeine Caffeine is rapidly absorbed–primarily from the small intestine, but also partially Caffeine