Adenosine: does it have a neuroprotective role after all?

Mendonça, Alexandre de; Sebastião, Ana M.; Ribeiro, Joaquim A.

doi:10.1016/s0165-0173(00)00033-3

Cited by 221 publications

(194 citation statements)

References 170 publications

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“…Data are representative of three independent experiments. and inflammation (Cunha, 2001;de Mendonca et al, 2000). Since ROS damages neurons directly or indirectly through the activation of inflammation (Whittemore et al, 1994;Qin et al, 2004), suppression of intracellular ROS may be an effective way to protect neurons.…”

Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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Adenosine, a purine nucleoside, has been reported to suppress the inflammatory responses of microglia in the brain. However, the underlying mechanisms of its anti-inflammatory action are unclear at present. Here we show that adenosine reduces the increase in intracellular reactive oxygen species (ROS) through expression of an antioxidant enzyme, hemeoxygenase-1 (HO-1). The H 2 O 2 -induced intracellular ROS level was significantly low in microglia pretreated with adenosine for 3-6 h, compared with that in untreated cells. Adenosine induced HO-1 mRNA and protein expression within 3 h, which was maintained for up to 12 h. Nuclear factor E2-related factor 2 (Nrf2), a transcription factor, and phosphatidylinositol 3-kinase (PI3K) and Akt pathways appear to mediate HO-1 expression. In response to adenosine, Nrf2 translocated from the cytosol to nuclei, and bound to the antioxidant response element (ARE). Adenosine enhanced HO-1 promoter activity in an ARE-dependent manner. Moreover, the nucleoside stimulated Akt phosphorylation, and suppressors of PI3K (LY294002 and wortmannin) reduced adenosine-induced HO-1 expression. However, we propose that the effects of adenosine are independent of adenosine receptors, since agonists and antagonists of A1, A2a, and A3 had little effect on the regulation of intracellular ROS and HO-1 expression. Our results collectively suggest that adenosine acts as an endogenous regulator of brain inflammation via modulation of microglial ROS production. V

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Section: Discussionmentioning

confidence: 99%

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Min

Kim

Jou

et al. 2008

Glia

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“…And, in fact, a diversity of studies in different brain preparations of different species using different noxious stimuli, consistently found that the acute activation of inhibitory A 1 Rs is neuroprotective (elegantly reviewed in [171]). Thus, in isolated neurons and in brain slices, A 1 R activation reduces damage to neurons, whereas A 1 R antagonists potentiate damage (reviewed in [171Y174]).…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

“…The first major drawback is due to the profound cardiovascular effects of A 1 R agonists (e.g., [178,179]), which are most worrying because A 1 R agonists have a poor brain permeability [180,181]. The second limitation is related to the short Fwindow of opportunity_ of A 1 R agonists, which is limited to a few hours, at most, after the initiation of the brain insult (reviewed in [171,173,174]; but see [182]). This is aggravated by the fact that is not conceivable to administer A 1 R agonists chronically (as a preventive strategy) because it causes an effect inversion, i.e.…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

“…Likewise, several studies showed that short periods of brain ischemia, which also trigger a robust increase in the extracellular levels of adenosine ( [121]; reviewed in [172]), produce a long-lasting decrease in the density of A 1 Rs in several brain regions (e.g., [200Y202]). Again, this hypoxia-induced homologous desensitization of A 1 Rs [203] is accompanied by a loss of efficiency of A 1 R agonists when applied more than one hour after the hypoxia period (reviewed in [171,173,174]; but see [182]). This homologous desensitization of A 1 Rs has also been documented in other situations which trigger the release of adenosine.…”

Section: Modification Of Adenosine Metabolism On Stressful Conditionsmentioning

confidence: 99%

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Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Cunha

2005

Purinergic Signalling

467

427

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Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A 1 receptors (A 1 Rs) and the less abundant, but widespread, facilitatory A 2A Rs. It is commonly assumed that A 1 Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A 1 R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A 1 Rs in chronic noxious situations. In contrast, A 2A Rs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A 2A R antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A 2A R antagonists as novel protective agents in neurodegenerative diseases such as Parkinson's and Alzheimer's disease, ischemic brain damage and epilepsy. The greater interest of A 2A R blockade compared to A 1 R activation does not mean that A 1 R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A 2A R antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A 1 Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.Abbreviations: Ab -b-amyloid peptide; A 1 Rs -A 1 receptors; A 2A Rs -A 2A

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“…Altogether, these physiological functions of adenosine operated through A 1 receptors provide a compelling rationale for this modulation system to fulfil a neuroprotective role in situations of brain damage (reviewed in de Mendonça et al, 2000). Interestingly, although the activation of A 1 receptors prevents or attenuates neuronal damage (de Mendonça et al, 2000), evidence is accumulating to suggest that the neuroprotection afforded by activation of A 1 receptors might be unrelated to its synaptic www.elsevier.com/locate/neuint Neurochemistry International 52 (2008) [65][66][67][68][69][70][71][72] effects and probably results from its extra-synaptic effects, in particular the decrease brain metabolism (Håberg et al, 2000;Duarte et al, 2005) and eventually the control of glia cells (reviewed in van Calker and Biber, 2005).…”

Section: Adenosine In the Brainmentioning

confidence: 99%

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

Cunha

2008

Neurochemistry International

145

129

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Adenosine is a prototypical neuromodulator, which mainly controls excitatory transmission through the activation of widespread inhibitory A 1 receptors and synaptically located A 2A receptors. It was long thought that the predominant A 1 receptor-meditated modulation by endogenous adenosine was a homeostatic process intrinsic to the synapse. New studies indicate that endogenous extracellular adenosine is originated as a consequence of the release of gliotransmitters, namely ATP, which sets a global inhibitory tonus in brain circuits rather than in a single synapse. Thus, this neuron-glia long-range communication can be viewed as a form of non-synaptic transmission (a concept introduced by Professor Sylvester Vizi), designed to reduce noise in a circuit. This neuron-glia-induced adenosine release is also responsible for exacerbating salient information through A 1 receptor-mediated heterosynaptic depression, whereby the activation of a particular synapse recruits a neuron-glia network to generate extracellular adenosine that inhibits neighbouring non-tetanised synapses. In parallel, the local activation of facilitatory A 2A receptors by adenosine, formed from ATP released only at high frequencies from neuronal vesicles, down-regulates A 1 receptors and facilitates plasticity selectively in the tetanised synapse. Thus, upon high-frequency firing of a given pathway, the combined exacerbation of global A 1 receptormediated inhibition in the circuit (heterosynaptic depression) with the local synaptic activation of A 2A receptors in the activated synapse, cooperate to maximise salience between the activated and non-tetanised synapses. #

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Adenosine: does it have a neuroprotective role after all?

Cited by 221 publications

References 170 publications

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Adenosine induces hemeoxygenase‐1 expression in microglia through the activation of phosphatidylinositol 3‐kinase and nuclear factor E2‐related factor 2

Neuroprotection by adenosine in the brain: From A1 receptor activation to A2A receptor blockade

Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

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