Neuroprotection by caffeine and adenosine A<sub>2A</sub> receptor blockade of <i>β</i>‐amyloid neurotoxicity

Dall'Igna, Oscar Phelippe Permigotti; Porciúncula, Lisiane O.; Souza, Diogo O.; Cunha, Rodrigo A.; Lara, Diogo R.

doi:10.1038/sj.bjp.0705185

Cited by 224 publications

(97 citation statements)

References 21 publications

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“…The neuroprotective properties of caffeine are attributable to several mechanisms, including its phosphodiesterase inhibition (Dall'lgna et al, 2003), but antagonism of adenosine receptors is also a recognized caffeine-related effect (Chou and Vickroy, 2003). Chronic caffeine treatment upregulates A1AR expression through chronic receptor antagonism (Shi et al, 1993) with improved outcomes after cerebral ischemia (Bona et al, 1995), possibly caused by the activation of downstream signaling molecules, including cAMP, protein kinase C, phosphatidylinositol-3 kinase, and MAP kinases (Linden, 2001).…”

Section: Discussionmentioning

confidence: 99%

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui¹,

Schnermann²,

Noorbakhsh³

et al. 2004

J. Neurosci.

298

265

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The neuromodulator adenosine regulates immune activation and neuronal survival through specific G-protein-coupled receptors expressed on macrophages and neurons, including the A1 adenosine receptor (A1AR). Here we show that A1AR null (A1AR Ϫ/Ϫ ) mice developed a severe progressive-relapsing form of experimental allergic encephalomyelitis (EAE) compared with their wild-type (A1AR ϩ/ϩ ) littermates. Worsened demyelination, axonal injury, and enhanced activation of microglia/macrophages were observed in A1AR Ϫ/Ϫ animals. In addition, spinal cords from A1AR Ϫ/Ϫ mice demonstrated increased proinflammatory gene expression during EAE, whereas anti-inflammatory genes were suppressed compared with A1AR ϩ/ϩ animals. Macrophages from A1AR Ϫ/Ϫ animals exhibited increased expression of the proinflammatory genes, interleukin-1␤, and matrix metalloproteinase-12 on immune activation when matched with A1AR ϩ/ϩ control cells. A1AR Ϫ/Ϫ macrophage-derived soluble factors caused significant oligodendrocyte cytotoxicity compared with wild-type controls. The A1AR was downregulated in microglia in A1AR ϩ/ϩ mice during EAE accompanied by neuroinflammation, which recapitulated findings in multiple sclerosis (MS) patients. Caffeine treatment augmented A1AR expression on microglia, with ensuing reduction of EAE severity, which was further enhanced by concomitant treatment with the A1AR agonist, adenosine amine congener. Thus, modulation of neuroinflammation by the A1AR represents a novel mechanism that provides new therapeutic opportunities for MS and other demyelinating diseases.

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Section: Discussionmentioning

confidence: 99%

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Tsutsui¹,

Schnermann²,

Noorbakhsh³

et al. 2004

J. Neurosci.

298

265

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“…Pharmacological and genetic A2a adenosine receptor deficiency studies have demonstrated that A2a inactivation protects against neuronal cell death induced by ischemia (Phillis, 1995;Monopoli et al, 1998;Chen et al, 1999), excitototoxicity (such as quinolinic acidinduced) (Jones et al, 1998;Popoli et al, 2002), the mitochondrial toxins 3-NP (an animal model of Huntington's disease) (Blum et al, 2003;Day et al, 2003), and b-amyloid aggregation (key neuropathological changes in Alzheimer's disease) in cultured cerebral granular cells (Dall'lgna et al, 2003). A broad neuroprotective effect supports the notion that endogenous adenosine acting at A2a adenosine receptors may in fact exacerbate brain tissue damage.…”

Section: A2a Adenosine Receptors A2aar Distribution and Signalingmentioning

confidence: 99%

Animal models for the study of adenosine receptor function

Yaar

Jones

Chen

et al. 2004

Journal Cellular Physiology

142

151

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Adenosine receptors represent a family of G-protein coupled receptors that are ubiquitously expressed in a wide variety of tissues. This family contains four receptor subtypes: A1 and A3, which mediate inhibition of adenylyl cyclase; and A2a and A2b, which mediate stimulation of this enzyme. Currently, all receptor subtypes have been genetically deleted in mouse models except for the A2b adenosine receptor, and some have been overexpressed in selective tissues of transgenic mice. Studies involving these transgenic mice indicated that receptor levels are rate limiting, as effects were amplified upon increases in receptor level. The knockout models pointed to clusters of activities related to the physiologies of the cardiovascular and the nervous systems, which are either reduced or enhanced upon specific receptor deletion. Interestingly, the trend of effects on these systems is similar in the A1 and A3 adenosine receptor knockout mice and opposite to the effects observed in the A2a adenosine receptor knockout model. This review summarizes in vitro studies on pathways affected by each adenosine receptor, and primarily focuses on the above in vivo models generated to investigate the physiologic role of adenosine receptors. Furthermore, it illustrates the need for multiple adenosine receptor subtype deficiency studies in mice and the deletion of the A2b subtype.

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“…Adenosine has been proposed as an endogenous neuroprotective agent in ischemia, stroke, epilepsy, Alzheimer's disease, and Parkinson's disease [13,32,53,61]. Adenosine receptor agonists have been reported to protect against ischemic cell death in vivo [2,11,14,66] and in vitro [22].…”

Section: Introductionmentioning

confidence: 99%

“…Adenosine receptor agonists have been reported to protect against ischemic cell death in vivo [2,11,14,66] and in vitro [22]. However, caffeine and adenosine A 2A receptor antagonists block β-amyloidinduced neurotoxicity in rat cultured cerebellar granule neurons [13]. Furthermore, in an animal model of Parkinson's disease, administration of A 2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6-hydroxydopamine in rats and prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice [32] Protein phosphorylation is one the most important signaling mechanisms regulating cellular function.…”

Section: Introductionmentioning

confidence: 99%

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

Rosenberg

2007

Brain Research

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We have previously demonstrated that NMDA receptor-mediated extracellular adenosine accumulation in neuronal cultures is receptor-mediated and requires calcium influx. Because protein kinase C (PKC) is a calcium-dependent enzyme, we hypothesized that activation of PKC might be involved in NMDA-mediated adenosine accumulation. PKC inhibitors however, did not block NMDA-evoked adenosine accumulation, but rather, stimulated basal adenosine accumulation. These data suggested the possibility that NMDA receptor mediated adenosine accumulation involves net dephosphorylation rather than phosphorylation of one or more substrates. Thus, inhibition of kinases would be expected to increase adenosine accumulation and inhibition of phosphatases would be expected to block adenosine accumulation. To test this hypothesis, we used the phosphatase 1/2A inhibitors calyculin A and okadaic acid. Both inhibitors significantly reduced NMDA-evoked adenosine accumulation. In contrast phosphatase 2B inhibitors did not block NMDA-evoked adenosine accumulation. These data suggest that NMDAevoked adenosine accumulation is mediated by activation of phosphatase 1/2A. We have established previously that NMDA-mediated adenosine accumulation is associated with adenosine kinase inhibition. However, adenosine kinase is not a direct substrate for phosphatase 1/2A because inhibition of phosphatase 1/2A did not abolish NMDA-evoked adenosine kinase inhibition. Okadaic acid also had no effect on NO donor-evoked adenosine accumulation, which previously has been shown to be associated with adenosine kinase inhibition. Dephosphorylation of one or more proteins other than adenosine kinase as a consequence of NMDA receptor activation might play an important role in extracellular adenosine regulation, with important consequences for the regulation of excitatory synaptic transmission, plasticity, epileptogenesis, and excitotoxicity.

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Neuroprotection by caffeine and adenosine A_2A receptor blockade of β‐amyloid neurotoxicity

Cited by 224 publications

References 21 publications

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Animal models for the study of adenosine receptor function

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

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Neuroprotection by caffeine and adenosine A2A receptor blockade of β‐amyloid neurotoxicity

Cited by 224 publications

References 21 publications

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

A1 Adenosine Receptor Upregulation and Activation Attenuates Neuroinflammation and Demyelination in a Model of Multiple Sclerosis

Animal models for the study of adenosine receptor function

NMDA receptor-mediated extracellular adenosine accumulation is blocked by phosphatase 1/2A inhibitors

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Neuroprotection by caffeine and adenosine A_2A receptor blockade of β‐amyloid neurotoxicity