Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis

Ng, Seng Kah; Higashimori, Haruki; Tolman, Michaela; Yang, Yongjie

doi:10.1016/j.expneurol.2015.03.004

Cited by 46 publications

(66 citation statements)

References 45 publications

(57 reference statements)

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“…Thus, specific A 2A R antagonists may represent a novel pharmacological strategy for controlling neurodegeneration in synucleinopathy. This neuroprotection against neurodegeneration in synucleinopathy is also in agreement with a broader spectrum of neuroprotection by A 2A R inactivation in the brain (Chen et al, 2007;Gomes et al, 2011), including animal models of ischemia (Chen et al, 1999), PD (Carta et al, 2009;Chen et al, 2001;Ikeda et al, 2002;Kachroo and Schwarzschild, 2012), AD (Canas et al, 2009b;Dall'Igna et al, 2007), tauopathy (Laurent et al, 2016), amyotrophic lateral sclerosis (Ng et al, 2015), Machado-Joseph disease (Goncalves et al, 2013), and traumatic brain injury (Dai et al, 2010).…”

Section: Accepted Manuscriptmentioning

confidence: 54%

“…It is known that A 2A R expression is sensitive to hypoxia (Kobayashi and Millhorn, 1999), inflammation and other brain insults that can trigger up-regulation of the A 2A R in different brain regions (Chen et al, 2013;Chen et al, 2014). Indeed, the A 2A R up-regulation has been documented in human brains of early PD (Villar-Menendez et al, 2014) and AD (Albasanz et al, 2008;Orr et al, 2015), and animal models of PD (Yu et al, 2008), AD (Orr et al, 2015), HD (Li et al, 2015b), amyotrophic lateral sclerosis (Ng et al, 2015), attention deficit hyperactivity disorder (Pandolfo et al, 2013), chronic unpredictable stress (Kaster et al, 2015). Notably, the upregulation of the A 2A R in disease models were demonstrated in neuronal (particularly the nerve terminals) (Kaster et al, 2015;Li et al, 2015b) and some glial elements (Orr et al, 2015;Yu et al, 2008).…”

Section: Syn Fibrils Into Non-transgenic Mice Markedly Increased Hippmentioning

confidence: 96%

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Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Ren

Liu

et al. 2016

Experimental Neurology

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Section: Accepted Manuscriptmentioning

confidence: 54%

Section: Syn Fibrils Into Non-transgenic Mice Markedly Increased Hippmentioning

confidence: 96%

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Ren

Liu

et al. 2016

Experimental Neurology

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“…On the other hand, astrocyte-derived adenosine is a candidate molecule involved in the cognitive deficits following sleep loss particularly at the hippocampal level [42, 43] and may have an important role in regulating blood-brain barrier permeability. Moreover, activation of A 2A receptor in astrocytes is related to activation of inflammatory status in several neuropathologies [44, 45]. In any case, gliosis is associated with blood-brain barrier disruption because the release of several inflammatory mediators [46–49]; however, it is also possible that glial cell activation may precede and even modify blood-brain barrier permeability, as shown after LPS administration [50].…”

Section: Discussionmentioning

confidence: 99%

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

et al. 2016

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Chronic sleep restriction induces blood-brain barrier disruption and increases pro-inflammatory mediators in rodents. Those inflammatory mediators may modulate the blood-brain barrier and constitute a link between sleep loss and blood-brain barrier physiology. We propose that adenosine action on its A2A receptor may be modulating the blood-brain barrier dynamics in sleep-restricted rats. We administrated a selective A2A adenosine receptor antagonist (SCH58261) in sleep-restricted rats at the 10th day of sleep restriction and evaluated the blood-brain barrier permeability to dextrans coupled to fluorescein (FITC-dextrans) and Evans blue. In addition, we evaluated by western blot the expression of tight junction proteins (claudin-5, occludin, ZO-1), adherens junction protein (E-cadherin), A2A adenosine receptor, adenosine-synthesizing enzyme (CD73), and neuroinflammatory markers (Iba-1 and GFAP) in the cerebral cortex, hippocampus, basal nuclei and cerebellar vermis. Sleep restriction increased blood-brain barrier permeability to FITC-dextrans and Evans blue, and the effect was reverted by the administration of SCH58261 in almost all brain regions, excluding the cerebellum. Sleep restriction increased the expression of A2A adenosine receptor only in the hippocampus and basal nuclei without changing the expression of CD73 in all brain regions. Sleep restriction reduced the expression of tight junction proteins in all brain regions, except in the cerebellum; and SCH58261 restored the levels of tight junction proteins in the cortex, hippocampus and basal nuclei. Finally, sleep restriction induced GFAP and Iba-1 overexpression that was attenuated with the administration of SCH58261. These data suggest that the action of adenosine on its A2A receptor may have a crucial role in blood-brain barrier dysfunction during sleep loss probably by direct modulation of brain endothelial cell permeability or through a mechanism that involves gliosis with subsequent inflammation and increased blood-brain barrier permeability.

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“…; Ng et al . ), diabetic neuropathy (Duarte et al . ), ataxia‐related Machado‐Joseph disease (Gonçalves et al .…”

Section: The Role Of A2ar In Neuroprotectionmentioning

confidence: 99%

How does adenosine control neuronal dysfunction and neurodegeneration?

Cunha

2016

Journal of Neurochemistry

343

374

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The adenosine modulation system mostly operates through inhibitory A 1 (A 1 R) and facilitatory A 2A receptors (A 2A R) in the brain. The activity-dependent release of adenosine acts as a brake of excitatory transmission through A 1 R, which are enriched in glutamatergic terminals. Adenosine sharpens salience of information encoding in neuronal circuits: highfrequency stimulation triggers ATP release in the 'activated' synapse, which is locally converted by ecto-nucleotidases into adenosine to selectively activate A 2A R; A 2A R switch off A 1 R and CB1 receptors, bolster glutamate release and NMDA receptors to assist increasing synaptic plasticity in the 'activated' synapse; the parallel engagement of the astrocytic syncytium releases adenosine further inhibiting neighboring synapses, thus sharpening the encoded plastic change. Brain insults trigger a large outflow of adenosine and ATP, as a danger signal. A 1 R are a hurdle for damage initiation, but they desensitize upon prolonged activation. However, if the insult is near-threshold and/or of short-duration, A 1 R trigger preconditioning, which may limit the spread of damage. Brain insults also up-regulate A 2A R, probably to bolster adaptive changes, but this heightens brain damage since A 2A R blockade affords neuroprotection in models of epilepsy, depression, Alzheimer's, or Parkinson's disease. This initially involves a control of synaptotoxicity by neuronal A 2A R, whereas astrocytic and microglia A 2A R might control the spread of damage. The A 2A R signaling mechanisms are largely unknown since A 2A R are pleiotropic, coupling to different G proteins and non-canonical pathways to control the viability of glutamatergic synapses, neuroinflammation, mitochondria function, and cytoskeleton dynamics. Thus, simultaneously bolstering A 1 R preconditioning and preventing excessive A 2A R function might afford maximal neuroprotection. Keywords: A 1 receptor, A 2A receptor, astrocyte, microglia, synaptic plasticity, synaptotoxicity. This article is part of a mini review series: "Synaptic Function and Dysfunction in Brain Diseases". Relevance of modulation systems to tune information flow in brain circuitsThe goal of understanding the flow of information in neuronal circuits has traditionally been centered in studying the key processes sustaining synaptic transmission and plasticity -i.e. the role of glutamate and glutamate receptors, as well as to a lesser extent the role of GABA and its receptors. If one considers an analogy to the experience of watching TV, this corresponds to studying how the ON/OFF button impacts all Received April 4, 2016; revised manuscript received May 23, 2016; accepted June 23, 2016. Address correspondence and reprint requests to R. A. Cunha, Center for Neurosciences and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal. E-mail: cunharod@gmail.com Abbreviations used: A 1 R, adenosine A 1 receptor; A 2A R, adenosine A 2A receptor; ADHD, attention deficit and hyperactivity disorder; BDNF, brain-derived neurotrophi...

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Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis

Cited by 46 publications

References 45 publications

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

Aberrant adenosine A2A receptor signaling contributes to neurodegeneration and cognitive impairments in a mouse model of synucleinopathy

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

How does adenosine control neuronal dysfunction and neurodegeneration?

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