Purinergic Signalling and Neurological Diseases: An Update

Burnstock, Geoffrey

doi:10.2174/1871527315666160922104848

Cited by 104 publications

(84 citation statements)

References 163 publications

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“…At a molecular level there are several explanatory theories of this UA metabolism dysfunction in BD. Increased levels of UA mean accelerated purinergic transformation and decreased adenosinergic transmission . As adenosinergic receptors (mostly A1 receptors) limit cellular excitability by inhibiting neurotransmitter's release in the central nervous system, the increase in serum UA levels found in subjects with BD as compared to other psychiatric disorders might account for the vulnerability of these subjects to the development of recurrences (trait vulnerability marker: the nervous system of subjects with BD would prove more vulnerable to affective episodes in response to stress because of a purinergic dysfunction—mania as a kindling‐like behavioral manifestation of purinergic dysfunction) .…”

Section: Discussionmentioning

confidence: 99%

Serum uric acid as a predictor of bipolarity in individuals with a major depressive episode

et al. 2018

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| INTRODUC TI ONBipolar Disorder (BD) is one of the top 20 leading causes of disability worldwide. 1 It affects more than 1% of the population, with an estimated lifetime prevalence of 0.6% for type I BD, 0.4% for type II BD, and 1.4% for subthreshold manifestations of BD. 2 Despite the availability of effective treatments, the delay between the onset of BD and its diagnosis and management is often very long, with a pooled interval of almost 6 years. 3 Early diagnosis is difficult in clinical practice because the onset of BD is often characterized by a Objectives: There are no well-established biomarkers to predict the risk of conversion to bipolar disorder (BD) in patients with depression. Given the putative role of purinergic neurotransmission dysfunction in BD, the purpose of our study was to evaluate if higher serum uric acid (UA) levels could predict BD conversion in depressed inpatients. Methods:We reviewed retrospectively the records of subjects hospitalized between June 2007 and June 2010 with a diagnosis of major depressive disorder (MDD) who had undergone routine UA levels testing at admission. At an approximate 10-year follow-up we identified subjects with a subsequent diagnosis of BD. We compared UA levels between the BD-converter and non-BD converter groups, performed Receiver operating characteristic curve analysis to evaluate the prognostic accuracy of serum UA levels and calculated the clinical utility index (CUI) as a risk biomarker for conversion to BD. Results:The study included 250 subjects (55 "BD-converters" and 195 "No BD-converters"). "BD-converters" had significantly higher plasma UA levels compared to "No BD-converters" in their index hospitalization irrespective of gender (males:403.84 ± 91.76 vs 270.81 ± 53.58 µmol/L; U = 94.5, P < 0.001 and females 302.19 ± 52.64 vs 202.69 ± 48.93 µmol/L; t = 10.75, P < 0.001). Serum UA levels showed a very good to excellent accuracy for predicting conversion to BD in inpatients with MDD (area under the curve [AUC]: 0.90; 95% CI: 0.86, 0.94) and had a good to excellent CUI− and a moderate to good CUI+ grading for discriminating BDconverter cases from non-BD converters. Conclusions:Our study suggests that depressed patients with higher levels of serum UA are at greater risk of a subsequent manic or hypomanic episode. The purinergic system could prove a promising path for the search of biomarkers in BD. K E Y W O R D Sbipolar disorder, major depressive disorder, uric acid

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Section: Discussionmentioning

confidence: 99%

Serum uric acid as a predictor of bipolarity in individuals with a major depressive episode

et al. 2018

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“…As previously mentioned, P2Y and P2X receptors modulate pain transmission (Burnstock, 2017). P2Y 1 , P2Y 2 , P2Y 12 and P2Y 13 receptors are expressed in nociceptive neurons and surrounding glial cells, and both pro‐nociceptive and pro‐analgesic effects have been proposed (Malin & Molliver, 2010).…”

Section: P2y Receptors In the Nervous Systemmentioning

confidence: 95%

“…P2Y receptors are especially abundant in glial cells, astrocytes and microglia, but they are also present in central and peripheral neurons, oligodendrocytes, and cerebral microvasculature. P2Y receptors together with ionotropic P2X receptors mediate neurotransmission, neuron–glia interaction, regulation of cerebral blood flow, and neuroprotection or even contribute to neurodegeneration and pain transmission (Burnstock, 2017; Toth et al, 2015; Weisman et al, 2012). P2Y receptors are also present in adult stem cells, which suggests potential actions in neuroregeneration (Gómez‐Villafuertes et al, 2015; Stefani et al, 2018).…”

Section: P2y Receptors In the Nervous Systemmentioning

confidence: 99%

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Update of P2Y receptor pharmacology: IUPHAR Review 27

Jacobson

Delicado

Gachet

et al. 2020

British J Pharmacology

170

184

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Eight G protein-coupled P2Y receptor subtypes respond to extracellular adenine and uracil mononucleotides and dinucleotides. P2Y receptors belong to the δ group of rhodopsin-like GPCRs and contain two structurally distinct subfamilies: P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , and P2Y 11 (principally G q protein-coupled P2Y 1 -like) and P2Y 12-14 (principally G i protein-coupled P2Y 12 -like) receptors. Brain P2Y receptors occur in neurons, glial cells, and vasculature. Endothelial P2Y 1 , P2Y 2 , P2Y 4 , and P2Y 6 receptors induce vasodilation, while smooth muscle P2Y 2 , P2Y 4 , and P2Y 6 receptor activation leads to vasoconstriction. Pancreatic P2Y 1 and P2Y 6 receptors stimulate while P2Y 13 receptors inhibits insulin secretion. Antagonists of P2Y 12 receptors, and potentially P2Y 1 receptors, are anti-thrombotic agents, and a P2Y 2 /P2Y 4 receptor agonist treats dry eye syndrome in Asia. P2Y receptor agonists are generally pro-inflammatory, and antagonists may eventually treat inflammatory conditions. This article reviews recent developments in P2Y receptor pharmacology (using synthetic agonists and antagonists), structure and biophysical properties (using X-ray crystallography, mutagenesis and modelling), physiological and pathophysiological roles, and present and potentially future therapeutic targeting.Abbreviations: BMD, bone mineral density; DUSP, dual specificity protein phosphatase; ECL, extracellular loop; EPAC, exchange protein activated by cAMP; KO, knockout; MSD, musculoskeletal disorder; SNP, single nucleotide polymorphism; SS, Sjögren's syndrome; TM, transmembrane helix.

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“…In response to extracellular ATP, the P2X 7 purinergic receptors may shift from rapid-gating channels selective for small cations to more slowly developing ''dilated pore'' conformations permeable to molecules up to 900 Da (North, 2002) and thus facilitate glutamate release under pathological conditions (Duan et al, 2003). In the CNS, these receptors were described in astrocytes, microglia, oligodendrocytes, and neurons (Hamilton et al, 2008;Grygorowicz et al, 2010;Burnstock, 2017); however, their precise role in glutamate excitotoxicity is not yet fully elucidated.…”

Section: Astrocytes Add Significantly To Glutamate Excitotoxicitymentioning

confidence: 99%

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

Kirdajová

Kriška

Tureckova

et al. 2020

Front. Cell. Neurosci.

246

150

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A plethora of neurological disorders shares a final common deadly pathway known as excitotoxicity. Among these disorders, ischemic injury is a prominent cause of death and disability worldwide. Brain ischemia stems from cardiac arrest or stroke, both responsible for insufficient blood supply to the brain parenchyma. Glucose and oxygen deficiency disrupts oxidative phosphorylation, which results in energy depletion and ionic imbalance, followed by cell membrane depolarization, calcium (Ca 2+ ) overload, and extracellular accumulation of excitatory amino acid glutamate. If tight physiological regulation fails to clear the surplus of this neurotransmitter, subsequent prolonged activation of glutamate receptors forms a vicious circle between elevated concentrations of intracellular Ca 2+ ions and aberrant glutamate release, aggravating the effect of this ischemic pathway. The activation of downstream Ca 2+ -dependent enzymes has a catastrophic impact on nervous tissue leading to cell death, accompanied by the formation of free radicals, edema, and inflammation. After decades of "neuron-centric" approaches, recent research has also finally shed some light on the role of glial cells in neurological diseases. It is becoming more and more evident that neurons and glia depend on each other. Neuronal cells, astrocytes, microglia, NG2 glia, and oligodendrocytes all have their roles in what is known as glutamate excitotoxicity. However, who is the main contributor to the ischemic pathway, and who is the unsuspecting victim? In this review article, we summarize the so-far-revealed roles of cells in the central nervous system, with particular attention to glial cells in ischemiainduced glutamate excitotoxicity, its origins, and consequences.

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Purinergic Signalling and Neurological Diseases: An Update

Cited by 104 publications

References 163 publications

Serum uric acid as a predictor of bipolarity in individuals with a major depressive episode

Serum uric acid as a predictor of bipolarity in individuals with a major depressive episode

Update of P2Y receptor pharmacology: IUPHAR Review 27

Ischemia-Triggered Glutamate Excitotoxicity From the Perspective of Glial Cells

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