Opposite modulation of astroglial proliferation by adenosine 5′-O-(2-thio)-diphosphate and 2-methylthioadenosine-5′-diphosphate: mechanisms involved

Quintas, Clara; Fraga, Sónia; Gonçalves, Jorge; Queiróz, Glória

doi:10.1016/j.neuroscience.2011.03.009

Cited by 21 publications

(26 citation statements)

References 52 publications

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“…The concentrationresponse curve to ATP was biphasic; it caused an increase in astroglial proliferation, mainly by activation of P2Y 1 , A 2A and A 2B receptors [11], but at the highest concentrations tested (0.3-1 mM), the proliferative response Table 2 Influence of conditioned medium from microglia cultures or co-cultures in the ADPβS-induced astroglial proliferation in highly enriched astroglial cultures declined, which may be explained by activation of inhibitory adenosine A 1 receptors [3] or by activation of P2X 7 receptors that have opposite effects to those of P2Y receptors in cell proliferation [40]. Several uracil nucleotides were also tested but did not change astroglial proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…The presence of microglia in cultures accelerated the metabolism of the intermediates, having a higher influence on ADP than on UDP metabolism. Therefore, in co-cultures, ADP was hardly detected, which can explain the loss of ATP proliferative effect, whereas in highly enriched astroglial cultures the accumulation of ADP favoured the activation of P2Y 1 receptors, which mediate astroglial proliferation [11]. However, the differences observed in the metabolism of UTP are insufficient to explain why it only caused inhibition of proliferation in co-cultures.…”

Section: Methyl-[mentioning

confidence: 95%

“…Therefore, based on previous studies indicating that ADPβS mediates astroglial proliferation by activation of P2Y 1 and P2Y 12 receptors [11], the possibility that differences in the expression of these P2Y receptor subtypes could explain the attenuation of ADPβS proliferative effect Values are means±SEM from four experiments. *P<0.05, significant differences from highly enriched astroglial cultures observed in co-cultures was investigated.…”

Section: Extracellular Metabolism Of Nucleotidesmentioning

confidence: 99%

“…P2Y receptors also mediate astrocyte migration [5] and modulate the release of cytokines [6,7] and prostaglandins [8], supporting the astroglial reactive phenotype observed during astrogliosis. In injury models, astroglial proliferation was found to be mediated by P2Y 1 receptors [9,10], and recently, we have shown that P2Y 12 receptors may also be involved in this response [11]. Additionally, nucleotides activate microglia P2 receptors which induce chemotaxis [12,13], phagocytosis [14], the release of trophic factors [15] and cytokines [16] that may have protective effects in cerebral injury [17,18].…”

Section: Introductionmentioning

confidence: 99%

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P2Y receptors on astrocytes and microglia mediate opposite effects in astroglial proliferation

Quintas

Fraga

Gonçalves

et al. 2011

Purinergic Signalling

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Nucleotides released upon brain injury signal to astrocytes and microglia playing an important role in astrogliosis, but the participation of microglia in the purinergic modulation of astrogliosis is still unclear. Highly enriched astroglial cultures and co-cultures of astrocytes and microglia were used to investigate the influence of microglia in the modulation of astroglial proliferation mediated by nucleotides. In highly enriched astroglial cultures, adenosine-5'-triphosphate (ATP), adenosine 5'-O-(3-thio)-triphosphate (ATPγS), adenosine 5'-O-(3-thio)-diphosphate (ADPβS; 0.01-1 mM), and adenosine-5'-diphosphate (ADP; 0.1-1 mM) increased proliferation up to 382%, an effect abolished in co-cultures containing 8% of microglia. The loss of ATP proliferative effect in co-cultures is supported by its fast metabolism and reduced ADP accumulation, an agonist of P2Y 1,12 receptors that mediate astroglial proliferation. No differences in ADPβS and ATPγS metabolism or P2Y 1,12 receptors expression were found in co-cultures that could explain the loss of their proliferative effect. However, conditioned medium from microglia cultures or co-cultures treated with ADPβS, when tested in highly enriched astroglial cultures, also prevented ADPβS proliferative effect. None of the uracil nucleotides tested had any effect in proliferation of highly enriched astroglial cultures, but uridine-5′-triphosphate (UTP; 0.1-1 mM) inhibited proliferation up to 66% in co-cultures, an effect that was dependent on uridine-5'-diphosphate (UDP) accumulation, coincident with a co-localization of P2Y 6 receptors in microglia and due to cell apoptosis. The results indicate that microglia control astroglial proliferation by preventing the proliferative response to adenine nucleotides and favouring an inhibitory effect of UTP/UDP. Several microglial P2Y receptors may be involved by inducing the release of messengers that restrain astrogliosis, a beneficial effect for neuronal repair mechanisms following brain injury.

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Section: Discussionmentioning

confidence: 99%

Section: Methyl-[mentioning

confidence: 95%

Section: Extracellular Metabolism Of Nucleotidesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

P2Y receptors on astrocytes and microglia mediate opposite effects in astroglial proliferation

Quintas

Fraga

Gonçalves

et al. 2011

Purinergic Signalling

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show abstract

“…The astroglial Ca 2þ signals in turn induce the secretion of ATP, thereby influencing neighbouring cells (Di Castro et al, 2011;Hamilton and Attwell, 2010). Under pathophysiological conditions, the involvement of the P2Y 1 R in the induction of astrogliosis was shown (Franke et al, 2009;Neary et al, 2003;Quintas et al, 2011). Moreover, the importance of purinergic signalling restoring the activity of neural circuits was demonstrated after injury (Chin et al, 2013;Choo et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

P2Y1 receptor mediated neuronal fibre outgrowth in organotypic brain slice co-cultures

et al. 2015

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Pathological Potential of Astroglial Purinergic Receptors

Franke

Illéš

2014

Glutamate and ATP at the Interface of Metabolism and Signaling in the Brain

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Acute brain injury and neurodegenerative disorders may result in astroglial activation. Astrocytes are able to determine the progression and outcome of these neuropathologies in a beneficial or detrimental way. Nucleotides, e.g. adenosine 5'-triphosphate (ATP), released after acute or chronic neuronal injury, are important mediators of glial activation and astrogliosis.Acute injury may cause significant changes in ATP balance, resulting in (1) a decline of intracellular ATP levels and (2) an increase in extracellular ATP concentrations via efflux from the intracellular space. The released ATP may have trophic effects, but can also act as a proinflammatory mediator or cytotoxic factor, inducing necrosis/apoptosis as a universal "danger" signal. Furthermore, ATP, primarily released from astrocytes, is a means of communication between neurons, glial cells, and intracerebral blood vessels.Astrocytes express a heterogeneous battery of purinergic ionotropic and metabotropic receptors (P2XRs and P2YRs, respectively) to respond to extracellular nucleotides.In this chapter, we summarize the contemporary knowledge on the pathological potential of P2Rs in relation to changes of astrocytic functions, determined by distinct molecular signaling cascades, in a variety of diseases. We discuss specific aspects of reactive astrogliosis, with respect to the involvement of prominent receptor subtypes, such as the P2X7 and P2Y1/2Rs. Examples of purinergic signaling of microglia, oligodendrocytes, and blood vessels under pathophysiological conditions will also be presented.The understanding of the pathological potential of purinergic signaling in "controlling and fine-tuning" of astrocytic responses is important for identifying possible therapeutic principles to treat acute and chronic central nervous system diseases.

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Opposite modulation of astroglial proliferation by adenosine 5′-O-(2-thio)-diphosphate and 2-methylthioadenosine-5′-diphosphate: mechanisms involved

Cited by 21 publications

References 52 publications

P2Y receptors on astrocytes and microglia mediate opposite effects in astroglial proliferation

P2Y receptors on astrocytes and microglia mediate opposite effects in astroglial proliferation

P2Y1 receptor mediated neuronal fibre outgrowth in organotypic brain slice co-cultures

Pathological Potential of Astroglial Purinergic Receptors

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