Modulation of glutamate release and excitotoxicity by adenosine A
            <sub>2A</sub>
            receptors

Popoli, Patrizia; Frank, Claudio; Tebano, Maria Teresa; Potenza, Rosa Luisa; Pintor, Annita; Domenici, Maria Rosaria; Nazzicone, Valeria; Pézzola, Antonella; Reggio, Rosaria

doi:10.1212/01.wnl.0000095216.89483.a2

Cited by 68 publications

(50 citation statements)

References 19 publications

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“…20 These data suggest that A3 receptors modulate protective responses during ischemic/ hypoxic brain injury. In this study, we found that A3 antagonist MRS1191 attenuated inosine-mediated protection, suggesting the activation of A3 receptors contributes to these protective effects of inosine in the CNS.Purinergic receptors have been reported to regulate glutamate release 21 and the response to excitatory amino acids. 22 We found that ischemia caused glutamate release in the ischemic cortex.…”

mentioning

confidence: 60%

Inosine Reduces Ischemic Brain Injury in Rats

Shen

Chen

Harvey

et al. 2005

Stroke

101

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Background and Purpose-Purinergic nucleoside inosine elicits protection and regeneration during various injuries. The purpose of this study was to examine the protective effects of inosine against cerebral ischemia. Methods-Adult Sprague-Dawley rats were anesthetized. Inosine, hypoxathine, or vehicle was administered intracerebroventricularly before transient right middle cerebral artery occlusion (MCAo). Animals were placed in behavioral chambers 2 days to 2 weeks after MCAo and then euthanized for tri-phenyl-tetrazolium chloride staining. Glutamate release was measured by microdialysis/high-performance liquid chromatography, and single-unit action potentials were recorded from neurons in the parietal cortex. Results-Stroke animals receiving inosine pretreatment demonstrated a higher level of locomotor activity and less cerebral infarction. Intracerebroventricular administration of the same dose of hypoxanthine did not confer protection. Coadministration of selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(Ϯ)-dihydropyridine-3,5-dicarboxylate (MRS1191) significantly reduced inosine-mediated protection. Inosine did not alter basal glutamate release, nor did it reduce ischemia-evoked glutamate overflow from cerebral cortex. However, inosine antagonized glutamate-induced electrophysiological excitation in cerebral cortical neurons. Key Words: inosine, adenosine Ⅲ neuroprotection Ⅲ stroke T he purinergic nucleoside inosine elicits protection and regeneration during various injuries. Inosine reduced zinc-induced injury in PC12 cells, 1 reduced toxicity after oxygen-glucose deprivation (OGD) in rat astrocyte cultures, 2 and preserved cell viability during chemical hypoxia induced by rotenone in spinal cord cell culture. 3 The protective effect of inosine has also been demonstrated in vivo. Infusion of inosine reduced ischemic/hypoxic injury in myocardium. 4 The roles of inosine in central nervous system (CNS) during ischemia have not been studied extensively. Middle cerebral artery occlusion (MCAo) led to release of inosine and its metabolite hypoxanthine from the ischemic cortex in stroke animals. 5 Inosine, given after stroke, stimulated axonal outgrowth and improved behavioral outcome in stroke animals. 6 These data suggest that inosine promotes neuroregeneration after stroke. It is still not clear whether inosine, given before cerebral ischemia, is neuroprotective. Conclusions-InosineSeveral protective mechanisms of inosine have been proposed from in vitro studies. Inosine binds selectively to A3, but not A1 or A2A, receptors in human embryonic kidney (HEK)-293 cells. Exogenous application of inosine increased ATP level in PC12 cells. Such an effect was not found with selective A1, A2A, or A3 agonists, indicating that the inosine-induced elevation of ATP levels did not relate to these purinergic receptors in PC12 cells. 7 Inosine or its analog inosine 5Ј-triphosphate reduced glutamate receptor-mediated responses in hippocampal CA1 synapse 8 or N-methyl-Daspartate-mediated n...

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mentioning

confidence: 60%

Inosine Reduces Ischemic Brain Injury in Rats

Shen

Chen

Harvey

et al. 2005

Stroke

101

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“…The A2AR located at these terminals can directly regulate the amount and frequency of glutamate release and outflow. 25 Our results suggest that the suppression of glutamate level may be responsible for the neuroprotective effect provided by A2AR deletion against bTBI in the acute stage, as has been described in other models of brain injury. 26 Failure to clear the synaptic cleft of glutamate can overstimulate postsynaptic glutamate receptors, promoting neuronal death.…”

Section: Inactivation Of A2a Receptor Preserves Cognitive Function Ansupporting

confidence: 77%

Adenosine A2A Receptor Deficiency Alleviates Blast-Induced Cognitive Dysfunction

Ning

Yang

Chen

et al. 2013

J Cereb Blood Flow Metab

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Traumatic brain injury (TBI), particularly explosive blast-induced TBI (bTBI), has become the most prevalent injury among military personnel. The disruption of cognitive function is one of the most serious consequences of bTBI because its long-lasting effects prevent survivors fulfilling their active duty and resuming normal civilian life. However, the mechanisms are poorly understood and there is no treatment available. This study investigated the effects of adenosine A2A receptor (A2AR) on bTBI-induced cognitive deficit, and explored the underlying mechanisms. After being subjected to moderate whole-body blast injury, mice lacking the A2AR (A2AR knockout (KO)) showed less severity and shorter duration of impaired spatial reference memory and working memory than wild-type mice did. In addition, bTBI-induced cortical and hippocampal lesions, as well as proinflammatory cytokine expression, glutamate release, edema, cell loss, and gliosis in both early and prolonged phases of the injury, were significantly attenuated in A2AR KO mice. The results suggest that early injury and chronic neuropathological damages are important mechanisms of bTBI-induced cognitive impairment, and that the impairment can be attenuated by preventing A2AR activation. These findings suggest that A2AR antagonism is a potential therapeutic strategy for mild-to-moderate bTBI and consequent cognitive impairment.

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“…In the CNS, glutamate can be released from presynaptic glutamatergic terminals such as corticostriatal terminals (Obrenovitch and Urenjak, 1997). The A 2A R at these terminals have been shown to modify the amount and frequency of glutamate release (Marchi et al, 2002;Popoli et al, 2003) and extracellular glutamate outflow in various brain regions (Popoli et al, 1995;Corsi et al, 1999). Another important source of extracellular glutamate in the brain likely come from glial cells, as suggested by studies showing that astrocytes release large amounts of glutamate by physiological astrocytic calcium levels and by inversion of glutamate transporter activity during hypoxia (Haydon and Carmignoto, 2006).…”

Section: Discussionmentioning

confidence: 99%