Caffeine and Its Neuroprotective Role in Ischemic Events: A Mechanism Dependent on Adenosine Receptors

Pereira-Figueiredo, Danniel; Nascimento, Amary; Cunha-Rodrigues, Marta C.; Brito, Rafael; Calaza, Karin da Costa

doi:10.1007/s10571-021-01077-4

Cited by 15 publications

(13 citation statements)

References 437 publications

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“…It modulates neuronal plasticity (Sebastiao and Ribeiro, 2015), astrocytic activity (Agostinho et al, 2020), learning and memory (Chen, 2014;Simoes et al, 2016;Bannon et al, 2017;Perrier et al, 2019;Temido-Ferreira et al, 2019;Zhang et al, 2020), food intake (Kola, 2008), motor function (Mori, 2020), sleep/wake cycle (Donlea et al, 2017;Lazarus et al, 2019), pain (Vincenzi et al, 2020), immunosupression (Vijayan et al, 2017), proliferation (Jacobson et al, 2019), and aging (Costenla et al, 2011). Adenosine is involved in ischemia and stroke (Williams-Karnesky and Stenzel-Poore, 2009;Melani et al, 2014;Pereira-Figueiredo et al, 2021), epilepsy (Boison and Jarvis, 2020;Tescarollo et al, 2020), and neurodegenerative pathologies such as Parkinson's disease (PD) (Fredholm and Svenningsson, 2020;Glaser et al, 2020), Alzheimer's disease (AD) (Rahman, 2009;Cunha and Agostinho, 2010;Cellai et al, 2018), amyotrophic lateral sclerosis (ALS) (Ng et al, 2015;Sebastiao et al, 2018), and Huntington's disease (HD) (Lee and Chern, 2014). Extracellular adenosine, interacting with P1 receptors (A1R, A2AR, A2BR, and A3R) regulates metabolism through different signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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Adenosine, acting both through G-protein coupled adenosine receptors and intracellularly, plays a complex role in multiple physiological and pathophysiological processes by modulating neuronal plasticity, astrocytic activity, learning and memory, motor function, feeding, control of sleep and aging. Adenosine is involved in stroke, epilepsy and neurodegenerative pathologies. Extracellular concentration of adenosine in the brain is tightly regulated. Adenosine may be generated intracellularly in the central nervous system from degradation of AMP or from the hydrolysis of S-adenosyl homocysteine, and then exit via bi-directional nucleoside transporters, or extracellularly by the metabolism of released nucleotides. Inactivation of extracellular adenosine occurs by transport into neurons or neighboring cells, followed by either phosphorylation to AMP by adenosine kinase or deamination to inosine by adenosine deaminase. Modulation of the nucleoside transporters or of the enzymatic activities involved in the metabolism of adenosine, by affecting the levels of this nucleoside and the activity of adenosine receptors, could have a role in the onset or the development of central nervous system disorders, and can also be target of drugs for their treatment. In this review, we focus on the contribution of 5′-nucleotidases, adenosine kinase, adenosine deaminase, AMP deaminase, AMP-activated protein kinase and nucleoside transporters in epilepsy, cognition, and neurodegenerative diseases with a particular attention on amyotrophic lateral sclerosis and Huntington’s disease. We include several examples of the involvement of components of the adenosine metabolism in learning and of the possible use of modulators of enzymes involved in adenosine metabolism or nucleoside transporters in the amelioration of cognition deficits.

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Section: Introductionmentioning

confidence: 99%

Metabolic Aspects of Adenosine Functions in the Brain

et al. 2021

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“…Ki values represent apparent Ki values for irreversibly binding ligands, determined as described in the Section 4. 2 Reference [22]. 3 Reference [37].…”

Section: Radioligand Bindingmentioning

confidence: 99%

“…ARs have been recognized as promising drug targets. The non-selective AR antagonists caffeine (I) and theophylline (II), bioactive constituents of coffee and tea, have been used for thousands of years as central stimulants (see Figure 1) [2]. Caffeine is applied in combination with acetylsalicylic acid and/or paracetamol for the treatment of pain [3], while theophylline is utilized for the therapy of asthma and bronchial inflammation [4].…”

Section: Introductionmentioning

confidence: 99%

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Irreversible Antagonists for the Adenosine A2B Receptor

et al. 2022

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Blockade of the adenosine A2B receptor (A2BAR) represents a potential novel strategy for the immunotherapy of cancer. In the present study, we designed, synthesized, and characterized irreversible A2BAR antagonists based on an 8-p-sulfophenylxanthine scaffold. Irreversible binding was confirmed in radioligand binding and bioluminescence resonance energy transfer(BRET)-based Gα15 protein activation assays by performing ligand wash-out and kinetic experiments. p-(1-Propylxanthin-8-yl)benzene sulfonyl fluoride (6a, PSB-21500) was the most potent and selective irreversible A2BAR antagonist of the present series with an apparent Ki value of 10.6 nM at the human A2BAR and >38-fold selectivity versus the other AR subtypes. The corresponding 3-cyclopropyl-substituted xanthine derivative 6c (PSB-21502) was similarly potent, but was non-selective versus A1- and A2AARs. Attachment of a reactive sulfonyl fluoride group to an elongated xanthine 8-substituent (12, Ki 7.37 nM) resulted in a potent, selective, reversibly binding antagonist. Based on previous docking studies, the lysine residue K2697.32 was proposed to react with the covalent antagonists. However, the mutant K269L behaved similarly to the wildtype A2BAR, indicating that 6a and related irreversible A2BAR antagonists do not interact with K2697.32. The new irreversible A2BAR antagonists will be useful tools and have the potential to be further developed as therapeutic drugs.

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“…However, the relative contribution of ATP- and adenosine-dependent neuronal signaling during neuroinflammation in driving or protecting against olfactory injury is unknown. Adenosine could potentially suppress neuronal excitability by restricting calcium influx and inhibiting glutamate release, eventually counteracting neuronal calcium overload ( Corradetti et al, 1984 ; Dunwiddie et al, 1984 ; Pereira-Figueiredo et al, 2021 ). This could be mediated presynaptically, as A 1 activation inhibits voltage-activated calcium channels (Ca v ) reducing transmitter exocytosis ( Banie and Nicholls, 1993 ; Zhu and Ikeda, 1993 ; Umemiya and Berger, 1994 ; Gundlfinger et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation

Schubert

Schulz

Träger

et al. 2022

Front. Cell. Neurosci.

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Adenine nucleotides, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), as well as the nucleoside adenosine are important modulators of neuronal function by engaging P1 and P2 purinergic receptors. In mitral cells, signaling of the G protein-coupled P1 receptor adenosine 1 receptor (A1R) affects the olfactory sensory pathway by regulating high voltage-activated calcium channels and two-pore domain potassium (K2P) channels. The inflammation of the central nervous system (CNS) impairs the olfactory function and gives rise to large amounts of extracellular ATP and adenosine, which act as pro-inflammatory and anti-inflammatory mediators, respectively. However, it is unclear whether neuronal A1R in the olfactory bulb modulates the sensory function and how this is impacted by inflammation. Here, we show that signaling via neuronal A1R is important for the physiological olfactory function, while it cannot counteract inflammation-induced hyperexcitability and olfactory deficit. Using neuron-specific A1R-deficient mice in patch-clamp recordings, we found that adenosine modulates spontaneous dendro-dendritic signaling in mitral and granule cells via A1R. Furthermore, neuronal A1R deficiency resulted in olfactory dysfunction in two separate olfactory tests. In mice with experimental autoimmune encephalomyelitis (EAE), we detected immune cell infiltration and microglia activation in the olfactory bulb as well as hyperexcitability of mitral cells and olfactory dysfunction. However, neuron-specific A1R activity was unable to attenuate glutamate excitotoxicity in the primary olfactory bulb neurons in vitro or EAE-induced olfactory dysfunction and disease severity in vivo. Together, we demonstrate that A1R modulates the dendro-dendritic inhibition (DDI) at the site of mitral and granule cells and impacts the processing of the olfactory sensory information, while A1R activity was unable to counteract inflammation-induced hyperexcitability.

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Caffeine and Its Neuroprotective Role in Ischemic Events: A Mechanism Dependent on Adenosine Receptors

Cited by 15 publications

References 437 publications

Metabolic Aspects of Adenosine Functions in the Brain

Metabolic Aspects of Adenosine Functions in the Brain

Irreversible Antagonists for the Adenosine A2B Receptor

Neuronal Adenosine A1 Receptor is Critical for Olfactory Function but Unable to Attenuate Olfactory Dysfunction in Neuroinflammation

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