Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man.

Lelo, Aznan; Birkett, D. J.; Robson, RA; Miners, John O.

doi:10.1111/j.1365-2125.1986.tb05246.x

Cited by 142 publications

(119 citation statements)

References 15 publications

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“…To perform this series of experiments, we employed an intermediate concentration of caffeine (100 μM) representing moderate to high levels of human use (Lelo et al 1986; Fredholm et al 1999). A single dose of bath‐perfused caffeine (100 μM, 5 min) induced a marked potentiation of the fEPSP slope (158.7 ± 12.9 percent; 5 min after caffeine; n = 12; N = 6; Fig.…”

Section: Resultsmentioning

confidence: 99%

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

et al. 2016

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Caffeine has cognitive‐enhancing properties with effects on learning and memory, concentration, arousal and mood. These effects imply changes at circuital and synaptic level, but the mechanism by which caffeine modifies synaptic plasticity remains elusive. Here we report that caffeine, at concentrations representing moderate to high levels of consumption in humans, induces an NMDA receptor‐independent form of LTP (CAFLTP) in the CA1 region of the hippocampus by promoting calcium‐dependent secretion of BDNF, which subsequently activates TrkB‐mediated signaling required for the expression of CAFLTP. Our data include the novel observation that insulin receptor substrate 2 (IRS2) is phosphorylated during induction of CAFLTP, a process that requires cytosolic free Ca2+. Consistent with the involvement of IRS2 signals in caffeine‐mediated synaptic plasticity, phosphorylation of Akt (Ser473) in response to LTP induction is defective in Irs2−/− mice, demonstrating that these plasticity changes are associated with downstream targets of the phosphoinositide 3‐kinase (PI3K) pathway. These findings indicate that TrkB‐IRS2 signals are essential for activation of PI3K during the induction of LTP by caffeine.

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Section: Resultsmentioning

confidence: 99%

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

et al. 2016

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“…On the other hand, the effects of theobromine have been less studied than those of caffeine, and the potential neurobiological effects of theobromine are still poorly understood [33,37], partially due to the prevalent idea that it is a weak central nervous system stimulant [38,39], and has only been showed to produce very minor subjective effects compared to caffeine [40]. In fact, while theobromine displays a longer half-life compared to caffeine (7.2 h against 4.1 h) [41], theobromine seems to be 2-to 3-fold less active than caffeine as an antagonist of the adenosine A 1 receptors in rat brain and at least 10-fold less active than caffeine as an antagonist of A 2A receptors [42]. However, theobromine may have other actions, independent on adenosine receptors blockade, as gene inducer or repressor [37].…”

Section: Discussionmentioning

confidence: 99%

Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline

Moreira

Diógenes

Mendonça

et al. 2016

JAD

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Abstract. Cocoa-related products like chocolate have taken an important place in our food habits and culture. In this work, we aim to examine the relationship between chocolate consumption and cognitive decline in an elderly cognitively healthy population. In the present longitudinal prospective study, a cohort of 531 participants aged 65 and over with normal MiniMental State Examination (MMSE; median 28) was selected. The median follow-up was 48 months. Dietary habits were evaluated at baseline. The MMSE was used to assess global cognitive function at baseline and at follow-up. Cognitive decline was defined by a decrease ≥ 2 points in the MMSE score between evaluations. Relative risk (RR) and 95% confidence interval (95%CI) estimates were adjusted for age, education, smoking, alcohol drinking, body mass index, hypertension, and diabetes. Chocolate intake was associated with a lower risk of cognitive decline (RR = 0.59, 95%CI 0.38-0.92). This protective effect was observed only among subjects with an average daily consumption of caffeine lower than 75 mg (69% of the participants; RR = 0.50, 95%CI 0.31-0.82). To our knowledge, this is the first prospective cohort study to show an inverse association between regular long-term chocolate consumption and cognitive decline in humans.

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“…Another in vitro study reported that caffeine could increase basal synaptic transmission and inhibit posttetanic potentiation, but did not affect LTP, at the same synapses; the concentrations of caffeine tested in these experiments were 500 µM and 10 mM [4]. Thus, the concentrations of caffeine used in these two studies were several orders of magnitude higher than the concentration of caffeine attained in the plasma in humans by ingestion of moderate amounts of coffee, estimated to be 5-70 µM (see [5][6][7][8]). The only pharmacological action known for caffeine at the low micromolar range is the antagonism of adenosine receptors, namely adenosine A 1 and A 2A receptors [9,10], and possibly adenosine A 3 receptors [11].…”

Section: Introductionmentioning

confidence: 94%

“…Upon HPLC evaluation (see e.g. [14]), these rats displayed a plasma concentration of caffeine of 32 ± 4 µM (n = 6), which is equivalent to the plasma concentration of caffeine found in humans consuming circa 6 cups of coffee daily [5,7,8]. In the same rats, the concentration of caffeine in the cerebrospinal fluid was lower than in the plasma, reaching a value of 23 ± 3 µM (n = 6).…”

Section: What Concentrations Should Be Tested To Reflect the Caffeinementioning

confidence: 99%

Caffeine, Adenosine Receptors, and Synaptic Plasticity

Costenla

Cunha

Mendonça

2010

JAD

112

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Abstract. Few studies to date have looked at the effects of caffeine on synaptic plasticity, and those that did used very high concentrations of caffeine, whereas the brain concentrations attained by regular coffee consumption in humans should be in the low micromolar range, where caffeine exerts pharmacological actions mainly by antagonizing adenosine receptors. Accordingly, rats drinking caffeine (1 g/L) for 3 weeks, displayed a concentration of caffeine of circa 22 µM in the hippocampus. It is known that selective adenosine A1 receptor antagonists facilitate, whereas selective adenosine A2A receptor antagonists attenuate, long term potentiation (LTP) in the hippocampus. Although caffeine is a non-selective antagonist of adenosine receptors, it attenuates frequency-induced LTP in hippocampal slices in a manner similar to selective adenosine A2A receptor antagonists. These effects of low micromolar concentration of caffeine (30 µM) are maintained in aged animals, which is important when a possible beneficial effect for caffeine in age-related cognitive decline is proposed. Future studies will still be required to confirm and detail the involvement of A1 and A2A receptors in the effects of caffeine on hippocampal synaptic plasticity, using both pharmacological and genetic approaches.

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Comparative pharmacokinetics of caffeine and its primary demethylated metabolites paraxanthine, theobromine and theophylline in man.

Cited by 142 publications

References 15 publications

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Caffeine‐mediated BDNF release regulates long‐term synaptic plasticity through activation of IRS2 signaling

Chocolate Consumption is Associated with a Lower Risk of Cognitive Decline

Caffeine, Adenosine Receptors, and Synaptic Plasticity

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