Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning.

Heurteaux, Catherine; Lauritzen, Inger; Widmann, Catherine; Lazdunski, Michel

doi:10.1073/pnas.92.10.4666

Cited by 515 publications

(324 citation statements)

References 43 publications

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“…It plays a direct protective role via regulation of neuronal survival [32]. It decreases inflammatory events in the CNS via the A2aR [23] and is neuroprotective in CNS ischemia via acting on A1 receptors [33,34]. Furthermore, ecto-5 0 -nucleotidase activity is upregulated in ischemic rat brains leading to increased protective purine synthesis [14].…”

Section: Discussionmentioning

confidence: 99%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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IFN-b treatment reduces the relapse rate in MS but its mechanism of action remains incompletely understood. Our aim was to clarify the beneficial effect of IFN-b in the treatment of MS. We assessed the influence of IFN-b treatment on (i) CD73 expression on the surface of primary cultures of human blood-brain barrier endothelial cells (BBB-EC) and human astrocytes using immunofluorescence staining and flow cytometry, (ii) transmigration of CD4 1 T lymphocytes using an in vitro model of BBB and (iii) CD73 enzyme activity, i.e. ecto-5 0 -nucleotidase activity in the serum of MS patients using a radiochemical assay. IFN-b increases the expression of ecto-5 0 -nucleotidase both on BBB-EC and astrocytes. As a consequence, lymphocyte transmigration through BBB-EC is reduced. Importantly, this reduction can be reversed using a,b-methyleneadenosine-5 0 -diphosphate, a specific inhibitor of ecto-5 0 -nucleotidase. CD73 is strongly expressed in microvasculature in samples of postmortem MS brain and, moreover, in the majority of MS patients there was a clear upregulation both in the soluble serum ecto-5 0 -nucleotidase activity and skin microvascular CD73 expression after IFN-b treatment. Upregulation of ecto-5 0 -nucleotidase and a subsequent increase in adenosine production might contribute to the beneficial effects of IFN-b on MS via enhancing the endothelial barrier function.Key words: Adenosine . Blood-brain barrier . CD73 . IFN-b . MS Introduction MS is a demyelinating disease characterized by perivascular inflammatory cell infiltrates in the white matter of the CNS. MS is generally thought to be an autoimmune disease in which the immune system attack against self-antigens results in inflammation and neurological symptoms [1]. First line treatment of MS is subcutaneous or intramuscular administration of IFN-b, which leads to a reduced number of relapses and a slower disease progression [2][3][4]. The proposed beneficial effects of IFN-b include a decrease in antigen presentation, MHC class II expression, T-cell proliferation, IFN-b production, ECM degradation, and the expression of adhesion molecules [5]. Moreover, recent reports describe IFN-b as a suppressor of both myeloid [6] and Th17-cells [7]. IFN-b also reduces the number of gadolinium enhancing lesions in brain magnetic resonance imaging of MS patients [2,3,8], which is thought to reflect its ability to regulate the blood-brain barrier (BBB) function [9]. Ecto-5 0 -nucleotidase (CD73; EC 3.1.3.5) is a 70 kDa GPI-anchored glycoprotein. It is abundantly expressed on vascular endothelium and subpopulations of lymphocytes, but not on granulocytes or monocytes [10] and it also circulates in blood in a soluble 2718form [11]. Ecto-5 0 -nucleotidase activity is found on many CNS cell types such as astrocytes, oligodendrocytes, microglial cells and brain EC in many species including human, rat, mouse and bovine [12][13][14][15]. CD73 modulates the extent of immune and inflammatory responses in vitro and in vivo. These effects are mediated via its enzymatic capability ...

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Section: Discussionmentioning

confidence: 99%

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Niemelä¹,

Ifergan²,

Yegutkin³

et al. 2008

Eur J Immunol

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“…Postsynaptically, adenosine increases conductances of various K ϩ -and Cl Ϫ -channels, which hyperpolarize the membrane potential and counteract a transmitter induced depolarisation with a subsequent reduction of Ca 2 ϩ -influx and stabilization of the Mg 2 ϩ blockage of NMDA receptors (Rudolphi et al 1992a,b;Rudolphi and Schubert 1996). Most, if not all, of these actions of adenosine are mediated via the adenosine A 1 receptor, whereas the role of the other adenosine receptor subtype in neuroprotection is less clear (Schubert et al 1997;Abbracchio and Cattabeni 1999;Heurteaux et al 1995). Accordingly, upregulation of adenosine A 1 receptors by chronic treatment with A 1 -antagonists increases the neuroprotective effect of adenosine (Sutherland et al 1991; Rudolphi et al 1992a,b).…”

mentioning

confidence: 99%

Interleukin-6 Enhances Expression of Adenosine A1 Receptor mRNA and Signaling in Cultured Rat Cortical Astrocytes and Brain Slices

Biber

2001

Neuropsychopharmacology

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The inhibitory neuromodulator adenosine is released in the brain in high concentrations under conditions of exaggerated neuronal activity such as ischemia and seizures, or electroconvulsive treatment. By inhibiting neural overactivity, adenosine counteracts seizure activity and promotes neuronal survival. Since stimulation of adenosineAdenosine, as a metabolite of ATP, nature's general energy source, has acquired early in evolution the general function of signaling and counteracting a dysbalance of energy supply and demand (Newby 1984). In the brain, adenosine acts as an inhibitory neuromodulator, which is released under conditions of neuronal activity and reduces this activity by inhibition of transmitter release and postsynaptic hyperpolarisation. Brain damage, e.g., by stroke, ischemia, and seizures leads to a pronounced increase in extracellular adenosine (for review see Rudolphi and Schubert 1996) which counteracts seizure activity (Dragunow 1988) and promotes neuronal survival (Deckert and Gleiter 1994;Picano and Abbracchio 1998;Dux et al. 1990).In addition to its role as an endogenous anticonvulsant and neuroprotective agent, adenosine is now recognized as an important regulator of sleep and wakefulness (for review see Porkka-Heiskanen 1999 (van Calker et al. 1978(van Calker et al. , 1979, but more recent findings have revealed coupling of adenosine receptors to other signaling systems including the phosphoinositol system, potassium, and calcium channels (for review see Fredholm et al. 1994;Ralevic and Burnstock 1998). Adenosine mediates neuroprotection by inhibiting presynaptically the release of several neurotransmitters including the excitatory neurotransmitter glutamate (Ribeiro 1995). Postsynaptically, adenosine increases conductances of various K ϩ -and Cl Ϫ -channels, which hyperpolarize the membrane potential and counteract a transmitter induced depolarisation with a subsequent reduction of Ca 2 ϩ -influx and stabilization of the Mg 2 ϩ blockage of NMDA receptors (Rudolphi et al. 1992a,b;Rudolphi and Schubert 1996). Most, if not all, of these actions of adenosine are mediated via the adenosine A 1 receptor, whereas the role of the other adenosine receptor subtype in neuroprotection is less clear (Schubert et al. 1997;Abbracchio and Cattabeni 1999;Heurteaux et al. 1995). Accordingly, upregulation of adenosine A 1 receptors by chronic treatment with A 1 -antagonists increases the neuroprotective effect of adenosine (Sutherland et al. 1991; Rudolphi et al. 1992a,b).Upregulation of adenosine A1-receptors is also observed after treatments that exert antidepressive effects in humans such as seizures and electroconvulsive treatment (ECT) (Newman et al. 1984;Gleiter et al. 1989;Angelatou et al..1993;Pagonopoulou et al. 1993), REM sleep deprivation (Yanik and Radulovacki 1987), and chronic treatment with carbamazepine (Daval et al. 1989;Biber et al. 1999;van Calker et al. 2000). While the upregulation by carbamazepine of adenosine A 1 receptors is readily comprehensible from carbamazepine's selective antag...

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“…Interestingly, the effect of ischemic preconditioning (IPC) of brain [15,16] was demonstrated before that of heart IPC [17] . Brain and heart share common signal transduction pathways, including activation of K ATP channel [18,19] .…”

Section: Introductionmentioning

confidence: 99%

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

et al. 2010

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Abstract:Objective Sevoflurane preconditioning has been demonstrated to reduce cerebral ischemia-reperfusion (IR) injury, but the underlying mechanisms have not been fully elucidated. Besides, different protocols would usually lead to different results. The objective of this study was to determine whether dual exposure to sevoflurane improves the effect of anesthetic preconditioning against oxygen and glucose deprivation (OGD) injury in vitro. Methods Rat hippocampal slices under normoxic conditions (95% O 2 /5% CO 2 ) were pre-exposed to sevoflurane 1, 2 and 3 minimum alveolar concentration (MAC) for 30 min, once or twice, with 15-min washout after each exposure. The slices were then subjected to 13-min OGD treatment (95% N 2 /5% CO 2 , glucose-free), followed by 30-min reoxygenation. The population spikes (PSs) were recorded in the CA1 region of rat hippocampus. The percentage of PS amplitude at the end of 30-min reoxygenation to that before OGD treatment was calculated, since it could indicate the recovery degree of neuronal function. In addition, to assess the role of mitogen-activated protein kinases (MAPKs) in preconditioning, U0126, an inhibitor of extracellular signal-regulated protein kinase (MEK-ERK1/2, ERK1/2 MAPK), and SB203580, an inhibitor of p38 MAPK, were separately added 10 min before sevoflurane exposure. Results Preconditioning once with sevoflurane 1, 2, and 3 MAC increased the percentage of PS amplitude at the end of 30-min reoxygenation to that before OGD treatment, from (15.13±3.79)% (control) to (31.88±5.36)%, (44.00±5.01)%, and (49.50±6.25)%, respectively, and twice preconditioning with sevoflurane 1, 2, and 3 MAC increased the percentage to (38.53±4.36)%, (50.74±7.05)% and (55.86±6.23)%, respectively. The effect of duplicate preconditioning with sevoflurane 3 MAC was blocked by U0126 [(16.23±4.62)%]. Conclusion Sevoflurane preconditioning can induce neuroprotection against OGD injury in vitro, and preconditioning twice enhances this effect. Besides, the activation of extracellular signal-regulated protein kinase (MEK-ERK1/2, ERK1/2 MAPK) may be involved in this process.

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Essential role of adenosine, adenosine A1 receptors, and ATP-sensitive K+ channels in cerebral ischemic preconditioning.

Cited by 515 publications

References 43 publications

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

IFN‐β regulates CD73 and adenosine expression at the blood–brain barrier

Interleukin-6 Enhances Expression of Adenosine A1 Receptor mRNA and Signaling in Cultured Rat Cortical Astrocytes and Brain Slices

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

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