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Unique Role of Caffeine Compared to Other Methylxanthines

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Unique Role of Caffeine Compared to Other Methylxanthines International Journal of Molecular Sciences Article Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells 1, 1, 1, 1 Daniel Janitschke y , Anna A. Lauer y , Cornel M. Bachmann y, Martin Seyfried , Heike S. Grimm 1, Tobias Hartmann 1,2 and Marcus O. W. Grimm 1,2,* 1 Experimental Neurology, Saarland University, 66421 Homburg/Saar, Germany; [email protected] (D.J.); [email protected] (A.A.L.); [email protected] (C.M.B.); [email protected] (M.S.); [email protected] (H.S.G.); [email protected] (T.H.) 2 Deutsches Institut für DemenzPrävention (DIDP), Saarland University, 66421 Homburg/Saar, Germany * Correspondence: [email protected] These authors contributed equally to this work. y Received: 3 November 2020; Accepted: 25 November 2020; Published: 27 November 2020 Abstract: Methylxanthines are a group of substances derived from the purine base xanthine with a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1 and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate the transcriptional regulation of 83 genes linked to Alzheimer’s disease in the presence of five methylxanthines, including the most prominent naturally occurring methylxanthines—caffeine, theophylline and theobromine—and the synthetic methylxanthines pentoxifylline and propentofylline. Methylxanthine-regulated genes were found in pathways involved in processes including oxidative stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene regulation for caffeine compared to the other methylxanthines, which was further substantiated by multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the replacement of single methylxanthines by others could result in unexpected effects, which could not be anticipated by the comparison to other substances in this substance class. Keywords: methylxanthines; caffeine; theobromine; theophylline; pentoxifylline; propentofylline; oxidative stress; lipid homeostasis; energy metabolism; signal transduction 1. Introduction Methylxanthines are derivatives of the purine base xanthine (2,6-dihydroxypurine) with additional methyl groups at the nitrogen of the xanthine structure (R1, R2, R3) (Figure1). The naturally occurring methylxanthine caffeine is characterized by three additional methyl groups (1,3,7-trimethylxanthine), whereas theophylline and theobromine have two additional methyl groups at different positions (theophylline = 1,3-dimethylxanthine; theobromine = 3,7-dimethylxanthine). Synthetic methylxanthines used as pharmaceuticals have, in addition to the methyl group at the R2 position, other functional groups Int. J. Mol. Sci. 2020, 21, 9015; doi:10.3390/ijms21239015 www.mdpi.com/journal/ijms Int.Int. J. Mol. J. Mol. Sci. Sci. 20202020, 21,,21 x ,FOR 9015 PEER REVIEW 2 of2 of21 19 addition to the methyl groups at R2 and R3, an oxohexyl group at R1 (3,7-dimethyl-1-(5- at the R1 and R3 positions. For example, pentoxifylline has, in addition to the methyl groups at R2 and oxohexyl)purin-2,6-dion), and propentofylline has a propylpurine group instead of a methyl group R3, an oxohexyl group at R1 (3,7-dimethyl-1-(5-oxohexyl)purin-2,6-dion), and propentofylline has a at R3 (3-methyl-1-(5-oxohexyl)-7-propylpurine-2,6-dione). propylpurine group instead of a methyl group at R3 (3-methyl-1-(5-oxohexyl)-7-propylpurine-2,6-dione). FigureFigure 1. 1.ChemicalChemical structure structure of ofxanthine xanthine (left (left) and) and combinations combinations of ofthe the side side chains chains of ofits its derivatives derivatives caffeine,caffeine, theophylline, theophylline, theobromine, theobromine, pentoxifylline pentoxifylline and and propentofylline propentofylline (right (right). ). TheThe naturally naturally occurring occurring methylxanthines methylxanthines caffeine, caffeine, theophylline theophylline and and theobromine theobromine are are widely widely consumedconsumed all all over over the the world, world, being being present present in incoffee, coffee, green green and and black black tea tea and and cacao cacao [1,2] [1,2. ].A Atotal total of of 81.2%81.2% of ofthe the participants participants in ina study a study investigating investigating time time trends trends of ofnon non-alcoholic-alcoholic beverage beverage intake intake among among GermanGerman citizens citizens declare declaredd aa frequentfrequent consumption consumption of coof ffcoffeeee [3]. [3] Co.ff eeCoffee and greenand green or black or teablack represent tea representthe second the most second commonly most consumedcommonly non-alcoholic consumed beverages,non-alcoholic after beverages water [4]., Methylxanthines after water [4] can. Methylxanthinesbe easily absorbed can frombe easily the digestive absorbed tract from after the oraldigestive intake tract and after are known oral intake to have and psychostimulant are known to haveactions psychostimulant [5,6]. actions [5,6]. AsideAside from from dietarydietary uptake, uptake, xanthine xanthine derivatives derivatives are or haveare beenor widelyhave usedbeen pharmacologically widely used pharmacologicallyin veterinary and in human veterinary medicine. and human For medicine. example, For methylxanthines example, methylxanthines are reported are to reported be beneficial to befor beneficial patients for with patients chronic with obstructive chronic obstructive lung disease lung (COPD) disease and(COPD) asthma and byasthma attenuating by attenuating bronchial bronchspasmsial spasms [7] and [7] for and the for treatment the treatment of respiratory of respiratory pediatric pediatric diseases diseases [ 8[8]].. Since Since methylxanthines methylxanthines cancan cross cross the the blood blood–brain–brain barrier barrier and and influence influence the the central central nervous nervous system system via via their their effect effect as as adenosineadenosine receptor receptor antagonists, antagonists, they they are are reported reported to tohave have benef beneficialicial properties properties in inrespect respect of ofneuronal neuronal andand neurodegenerative neurodegenerative disorders disorders like like schizophrenia, schizophrenia, Parkinson´s Parkinson’s disease disease and and Alzheimer´s Alzheimer’s disease disease (AD)(AD) [9[9––11]11]. .In respectrespect to to coronary coronary heart heart diseases, diseases methylxanthines, methylxanthines are reported are toreported prevent hypertension,to prevent hypertension,arterial thrombosis arterial andthrom myocardialbosis and infarction, myocardial as infarction they have, beenas they shown have to been affect shown platelet to functionaffect plateletand arterial function vasodilation and arterial[7 vasodilation,12]. In addition [7,12] to. In their addition beneficial to the eirff ectsbeneficial in treating effects the in sidetreat eingffects theof sideradiotherapy, effects of radiotherapy individual methylxanthines, individual methylxanthines are reported are to be reported useful forto be biochemical useful for modulationbiochemical of modulationcancer chemotherapy of cancer chemotherapy [13]. [13]. MethylxanthinesMethylxanthines act act via via different different mechanisms mechanisms,, including including antagonism antagonism of ofpurinergic purinergic P1 P1 receptors, receptors, mainlymainly adenosine adenosine A1 A1 and and A2A A2A receptors receptors [14] [14. ].Blocking Blocking adenosine adenosine receptors receptors reduces reduces inhibitory inhibitory endogenousendogenous adenosine adenosine and and modulates modulates several several cellular cellular pathways pathways,, e.g. e.g.,, by by increas increasinging dopaminergic dopaminergic activityactivity in inthe the brain brain and and thereby thereby mediating mediating the the psychostimulant psychostimulant effect. effect. In Inhigher higher concentrations, concentrations, whichwhich cannot cannot be reached be reached by nutritional by nutritional intake, intake, but rather but are rather reached are reachedthrough throughpharmaceutical pharmaceutical intake, methylxanthinesintake, methylxanthines lead to inhibition lead to inhibition of cyclic ofnucleotide cyclic nucleotide phosphodiesterases phosphodiesterases and high and-affinity high-a ATPffinity- dependentATP-dependent cyclic nucleotide cyclic nucleotide transporters transporters,, resulting resulting in an increase in an increase of cellular of cellular cyclic AMP cyclic levels AMP levelsand mobilizand mobilizationation of intracellular of intracellular calcium; calcium; as a consequence as a consequence a modulation a modulation of gamma of gamma-amino-amino butyric butyric acid receptorsacid receptors,, for example, for example, has been has reported been reported [15–18] [15. –18]. MethylxanthinesMethylxanthines affect affect gene gene transcription transcription via via different different mechanisms. mechanisms. Naturally Naturally occurring occurring methylxanthinesmethylxanthines effectively effectively
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