The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil

Phillis, John W.

doi:10.1016/0006-8993(95)01153-6

Cited by 151 publications

(88 citation statements)

References 45 publications

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“…DPCPX has demonstrated efficacy in reaching the brain parenchyma and inhibiting A 1 R activity in the brain (Phillis, 1995). DPCPX abolished the protective effects of CX3CL1 (as shown Fig.…”

Section: Cx3cl1-mediated Neuroprotection Requires the Activation Of Amentioning

confidence: 64%

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CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

Cipriani¹,

Villa²,

Chece³

et al. 2011

J. Neurosci.

162

147

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The chemokine CX3CL1 and its receptor CX3CR1 are constitutively expressed in the nervous system. In this study, we used in vivo murine models of permanent middle cerebral artery occlusion (pMCAO) to investigate the protective potential of CX3CL1. We report that exogenous CX3CL1 reduced ischemia-induced cerebral infarct size, neurological deficits, and caspase-3 activation. CX3CL1-induced neuroprotective effects were long lasting, being observed up to 50 d after pMCAO in rats. The neuroprotective action of CX3CL1 in different models of brain injuries is mediated by its inhibitory activity on microglia and, in vitro, requires the activation of adenosine receptor 1 (A 1 R). We show that, in the presence of the A 1 R antagonist 1,3-dipropyl-8-cyclopentylxanthine and in A 1 R ؊/؊ mice, the neuroprotective effect of CX3CL1 on pMCAO was abolished, indicating the critical importance of the adenosine system in CX3CL1 protection also in vivo. In apparent contrast with the above reported data but in agreement with previous findings, cx3cl1 ؊/؊ and cx3cr1 GFP/GFP mice, respectively, deficient in CX3CL1 or CX3CR1, had less severe brain injury on pMCAO, and the administration of exogenous CX3CL1 increased brain damage in cx3cl1 ؊/؊ ischemic mice. We also report that CX3CL1 induced a different phagocytic activity in wild type and cx3cl1 ؊/؊ microglia in vitro during cotreatment with the medium conditioned by neurons damaged by oxygenglucose deprivation. Together, these data suggest that acute administration of CX3CL1 reduces ischemic damage via an adenosinedependent mechanism and that the absence of constitutive CX3CL1-CX3CR1 signaling changes the outcome of microglia-mediated effects during CX3CL1 administration to ischemic brain.

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Section: Cx3cl1-mediated Neuroprotection Requires the Activation Of Amentioning

confidence: 64%

“…A constant rate of infusion (0.2 l/min) was maintained with a pump (KD Scientific). DPCPX (0.1 mg/kg; Phillis, 1995) and DMSO (vehicle, 0.5 ml/kg) were given intraperitoneally 30 min before CX3CL1 or saline in rats. Sham-operated animals received only vehicles.…”

Section: Drugs and Administration Protocolsmentioning

confidence: 99%

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

Cipriani¹,

Villa²,

Chece³

et al. 2011

J. Neurosci.

162

147

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“…But the first report by Phillis' group that a non-selective A 2A R antagonist (CGS 15943) attenuated cerebral ischemic injury [225], in contrast to A 1 R antagonists [226], appeared as a serendipitous observation. Similar observations were made by von Lubitz in a similar gerbil model of brain ischemia [227].…”

Section: A 2a Receptor Blockade Confers Robust Neuroprotectionmentioning

confidence: 99%

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

Cunha

2005

Purinergic Signalling

470

428

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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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“…On the one hand, A 2A R inactivation can protect the brain against various insults including ischemia, excitotoxicity, and mitochondrial toxicity (Cunha, 2005). For example, genetic and pharmacological inactivation of A 2A Rs downregulates neuroinflammation and protects brain tissue against ischemia (Phillis, 1995;Chen et al, 1999), the dopaminergic neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and 6-OHDA (6-hydroxydopamine) (Chen et al, 2001;Ikeda et al, 2002;Yu et al, 2008), excitotoxicity (Jones et al, 1998a,b;Popoli et al, 2002), ␤-amyloid aggregation (Dall'Igna et al, 2007;Canas et al, 2009), and traumatic brain injury (TBI) (Li et al, 2009). The protective effect of A 2A R inactivation in the brain has been attributed to inhibition of glutamate release and suppression of proinflammatory cytokines (Popoli et al, 1995Yu et al, 2004;Cunha, 2005;Chen et al, 2007;Stone and Behan, 2007).…”

Section: Introductionmentioning

confidence: 99%

Local Glutamate Level Dictates Adenosine A_2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

Dai¹,

Zhou²,

Li³

et al. 2010

J. Neurosci.

145

120

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The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil

Cited by 151 publications

References 45 publications

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

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

Local Glutamate Level Dictates Adenosine A_2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

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The effects of selective A1 and A2a adenosine receptor antagonists on cerebral ischemic injury in the gerbil

Cited by 151 publications

References 45 publications

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

CX3CL1 Is Neuroprotective in Permanent Focal Cerebral Ischemia in Rodents

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

Local Glutamate Level Dictates Adenosine A2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury

Contact Info

Product

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Local Glutamate Level Dictates Adenosine A_2AReceptor Regulation of Neuroinflammation and Traumatic Brain Injury