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Neuroscience Letters xxx (2013) xxx– xxx

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Neuroscience Letters

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ucleotide signaling in astrogliosis

eike Franke, Peter Illes ∗

udolf-Boehm-Institute of Pharmacology and Toxicology, University of Leipzig, 04107 Leipzig, Germany

i g h l i g h t s

ATP is released by various mechanisms following acute and chronic damage to the central nervous system.Extracellular ATP activates P2X and P2Y receptors at astrocytes.Activation of astrocytic P2X and P2Y receptors induced astrogliosis.

r t i c l e i n f o

rticle history:eceived 17 August 2013eceived in revised form 5 September 2013ccepted 17 September 2013

eywords:strogliosisucleotides2 receptorsraumatic CNS injurytrokeeuroinflammation

a b s t r a c t

Acute and chronic damage to the central nervous system (CNS) releases large quantities of ATP. Whereasthe ATP concentration in the extracellular space is normally in the micromolar range, under these condi-tions it increases to millimolar levels. A number of ligand-gated cationic channels termed P2X receptors(7 mammalian subtypes), and G protein-coupled P2Y receptors (8 mammalian subtypes) are located atastrocytes, as confirmed by the measurement of the respective mRNA and protein. Activation of both theP2X7 and P2Y1,2 subtypes identified at astrocytes initiates astrogliosis isolating damaged brain areas fromsurrounding healthy cells and synthesizing neurotrophins and pleotrophins that participate in neuronalrecovery. Astrocytes are considered as cells of high plasticity which may alter their properties in a culturemedium. Therefore, recent work concentrates on investigating nucleotide effects at in situ (acute brainslices) and in vivo astrocytes. A wealth of data relates to the involvement of purinergic mechanisms inastrogliosis induced by acute CNS injury such as mechanical trauma and hypoxia/ischemia. The releasedATP may act within minutes as an excitotoxic molecule; at a longer time-scale within days it causes
neuroinflammation. These effects sum up as necrosis/apoptosis on the one hand and proliferation onthe other. Although the role of nucleotides in chronic neurodegenerative illnesses is not quite clear, itappears that they aggravate the consequences of the primary disease. Epilepsy and neuropathic pain arealso associated with the release of ATP and a pathologic glia-neuron interaction leading to astrogliosisand cell death. In view of these considerations, P2 receptor antagonists may open new therapeutic vistasin all forms of acute and chronic CNS damage.
© 2013 Elsevier Ireland Ltd. All rights reserved.

ontents

1. Astrogliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. The release of ATP, its inactivation, and ATP-sensitive receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Nucleotide effects at astrocytes and second-messenger pathways . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. ATP as a stimulus for astrogliosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. Acute damage to astrocytes and its chronic consequences; trauma and ischemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Please cite this article in press as: H. Franke, P. Illes, Nhttp://dx.doi.org/10.1016/j.neulet.2013.09.056

6. Chronic damage to astrocytes; neurodegenerative illnesses, epilepsy, an7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

∗ Corresponding author at: Rudolf-Boehm-Institute of Pharmacology and Toxicology, Uel.: +49 341 9724614; fax: +49 341 9724609.

E-mail addresses: [email protected], [email protected] (P. Il

304-3940/$ – see front matter © 2013 Elsevier Ireland Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.neulet.2013.09.056

ucleotide signaling in astrogliosis, Neurosci. Lett. (2013),

d neuropathic pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

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niversity of Leipzig, Haertelstrasse 16-18, 04107 Leipzig, Germany.

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dx.doi.org/10.1016/j.neulet.2013.09.056


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H. Franke, P. Illes / Neurosc

. Astrogliosis

Astrogliosis is a pathological hallmark of CNS injury char-cterized by profound morphological, molecular and functionalhanges in astrocytes that occur within hours and evolvess time elapses after injury [e.g. 25,48,64,66]. It is a defenceechanism to minimize and repair the initial damage but even-

ually leads to some detrimental effects. Although it is generallyccepted that activated (reactive) astrocytes contribute to iso-ating damaged brain areas from surrounding healthy cells andynthesize neurotrophins and pleotrophins that participate ineuronal recovery, these cells also release several potentiallyoxic compounds (e.g. nitric oxide and arachidonic acid metabo-ites) [53,74]. In severe cases, astrogliosis results in the formationf irreversible glial scarring that acts as regeneration barrier25,64,66].

Various glial cells and cellular signals are involved in the forma-ion of the glial scar. Within the first few hours after CNS damage,euronal and glial cells undergo cell death at the injury site with

concurrent recruitment of microglia and peripheral monocytesincluding macrophages) [16]. Astrocytes migrate from the adja-ent undamaged parenchyma towards the injured area and starteparation for example by protruding processes into the injury core61].

. The release of ATP, its inactivation, and ATP-sensitiveeceptors

During physiological conditions, the concentration of extra-ellular ATP is in the micromolar range [31,43], but underathological conditions such as ischemia and cellular injury, itan reach millimolar levels. ATP can be released by exocyto-is – as a transmitter of its own right or a co-transmitter oflassic transmitters – from the nerve terminals of central anderipheral neurons [9]. In addition, ATP and other nucleotidesay leave the intracellular space of astrocytes by exocytotic

esicular release (gliotransmission), ATP-binding cassette proteins,onnexin-hemichannels, osmolytic transporters linked to anionhannels, and finally via the ATP-sensitive P2X7 receptor-subtype3,31]. ATP may be degraded by a family of ectonucleotidasesiffering in their substrate specificity and product formation62,84].

The effects of nucleotides are mediated by two classes of2 receptors, termed P2X (ligand-gated cationic channels) and2Y (G protein-coupled receptors) [2,56]. In mammalian tis-ues, 7 homomeric P2X (P2X1-7) and 8 P2Y (P2Y1,2,4,6,11,12,13,14)eceptors were identified; individual P2X subunits may alsoorm heteromeric assemblies, combining the pharmacological andiophysical properties of their subunits [56]. Adenosine maye generated either by the enzymatic degradation of extra-ellular ATP or may pass the cell membrane from the intra-o the extracellular space mainly by utilizing reverse modeucleoside transporters [31]). Adenosine acts via 4 types of G-rotein-coupled receptors (A1,2A,2B,3; [6]). Adenosine receptorsere shown to directly [8] or indirectly (by the modula-

ion of pathological conditions fostering adenosine release;6]) interfere with astrogliosis. Furthermore, P2Y-like deor-hanized receptors (e.g. GPR17), dually responding to uracilucleotides (UDP, UDP-glucose) and arachidonic acid-derivedysteinyl-leukotrienes (LTD4, LTE4) have been reported to modu-ate proliferation of oligodendrocytes and possibly also astrocytes


26]. Nonetheless, in this review we will concentrate onhe involvement of classic nucleotide-sensitive P2 rather thanucleoside-sensitive P1 receptors in astrocytic proliferation andamage.

PRESSLetters xxx (2013) xxx– xxx

3. Nucleotide effects at astrocytes and second-messengerpathways

Astrocytes are endowed both with P2X and P2Y receptors. Pri-mary cultured astrocytes prepared from various areas of the brainand spinal cord express mRNA and protein for a number of P2Yreceptor-subtypes (Fig. 1) [18,73]. In consequence, treatment ofcultured astrocytes with ATP induced [Ca2+]i transients, whichwere as a rule caused by P2Y receptor activation, production ofinositol 3,4,5 trisphosphate (InsP3) and subsequent Ca2+ releasefrom the endoplasmic reticulum [18,72]. The imaging of [Ca2+]iby means of fluorescent dyes is thereby a reliable technique toprove the immediate consequences of P2Y receptor activation. Thereaction chain triggered in astrocytes by the activation of P2Y1,2receptor-subtypes can be phospholipase C (PLC) dependent Ca2+

mobilization, measured as [Ca2+]i transients [11,27]. Release of ATPfrom astrocytes may be an important mechanism contributing tothe propagation of glial Ca2+ waves in a quasi syncytial tissue [29].

There was an intensive debate, whether P2X receptors are alsopresent on in situ astrocytes, in spite of confirming the existence ofthe respective mRNA and protein in astroglia kept in primary cul-ture [32]. It was argued that electrophysiological techniques whichare capable of recording cationic currents through the astroglialmembrane in acute brain slices or dissociated astrocytes failedto yield unequivocal results. In the hippocampus [34] or cere-bral cortex [45] of the transgenic Tg(GFAP/EGFP) mice, expressingenhanced green fluorescence protein (EGFP) under the control ofthe human glial fibrillary acidic protein (GFAP; a marker of astro-cytes), no or unpredictable and non-reproducible responses ofastrocytes to high concentrations of ATP were observed. However,a re-investigation of these results showed that both in the pre-frontal cortex and hippocampus, astrocytes respond to ATP and theprototypic P2X7 receptor agonist dibenzoyl ATP (Bz-ATP), and theinward currents were largely increased in a low Ca2+/no Mg2+ (lowX2+) bath medium (Fig. 2A) [59]. Bz-ATP had a higher potency thanATP itself (Fig. 2B) and selective P2X7 receptor antagonists stronglyinhibited the effect of Bz-ATP in astrocytes obtained from wild-typemice (Fig. 2C). By contrast, there was no agonist effect in astrocytesobtained from P2X7 receptor-deficient mice. In accordance withthese latter findings, cultured astroglial cells from rats and micehave been reported to react to ATP/Bz-ATP with current responsesblocked by P2X7 receptor antagonists [15,57].

Astrocytic P2X1/5, but also P2X7 receptors are entry routes forextracellular Na+ and Ca2+, thereby regulating numerous functionssuch as focal exocytosis to release gliotransmitters, local stimu-lation of ATP production in mitochondria, inhibition of glutamatetransporter and stimulation of the lactate shuttle to supply energysubstrate for neurons [32,73]. The above mentioned specific sub-type of the P2X receptor, P2X7 massively increases intracellularCa2+ and thereby stimulates common intracellular messenger path-ways also triggered by P2Y receptor-activation, which initiate geneexpression in the cell nucleus (Fig. 3) [32]. Moreover, P2X7 recep-tors activate the caspase cascade resulting in apoptosis and inducerelease of the inflammatory cytokine interleukine-1� (IL-1�), aswell as they increase the production and release of NO and free oxy-gen radicals (ROS) [67]. Further properties of P2X7 receptors put itin the centre of the orchestration of necrotic effects in astrocytes;they dilate on longer-lasting contact with large concentrations ofATP (or open membrane pores after recruiting accessory proteinsprobably pannexin 1 [47]) and interfere with the cytoskeletal struc-ture by causing membrane blebbing [63].

ATP release from astrocytes is certainly important in glial-


glial signaling (propagation of Ca2+ waves within the astrocyticsyncytium) and in glial-neuronal reciprocal communications (mod-ulation of transmitter release, regulation of synaptic plasticity)[35,43]. During physiological signaling, small and transient increase


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Fig. 1. Confocal images of double immunofluorescence to characterize the localization of P2Y receptor-subtypes on astroglia (primary glial-neuronal co-cultures). Repre-sentative examples of double immunofluorescence of P2Y receptor-subtypes (Cy3, red) and GFAP (Cy2, yellow-green) in astroglia. Immunoreactivity was found for P2Y1 (A),P2Y2 (B), P2Y4 (C), P2Y6 (D), P2Y13 (F) and P2Y14 (G) receptor-subtypes, but not for P2Y12 (E). One representative example for a control image (pre-adsorption of the anti-P2Y4

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n extracellular levels of ATP principally activate the respective glialeceptors involved in interglial communication, coupling and co-rdination of glial and neuronal functions. Specifically, glial cellseem to be involved in certain feedback mechanisms. They carry

number of transmitter receptors (including those for ATP) andeply to neuronal activity by increasing their intracellular Ca2+,hich subsequently stimulates the release of gliotransmitters toodulate neuronal activity [5]. Glutamate and ATP are suggested

o be important mediators in the cross-talk between neurons andlial cells [41]. Indeed, ATP via P2Y receptors facilitates glutamateelease from astrocytes in various brain regions and in the spinalord [79]. P2X7 receptor-channels trigger the release of glutamatend ATP itself from astrocytes in the hippocampus [15].

However, during pathological states (after injury or duringnflammation), massive release of ATP causes larger and more pro-onged increases in intracellular Ca2+ which is sufficient to initiatend amplify the inflammatory responses – with the involvement ofctivated microglia – contributing to neural damage. Pathophysi-


logically high ATP concentrations activate P2Y and P2X receptorsn concert. P2Y receptors linked to the mitogen-activated pro-ein kinase (MAPK)/extracellular signal-regulated protein kinaseERK) and cyclooxygenase-2 (COX-2) pathways have prominent

-fluorescence alone was given for the P2Y4 receptor (Ca–d). (For interpretation ofticle.)

roles in contributing to neuroinflammation [7,54]. P2Y1 receptorsmediate the effects of ATP on IL-1�-induced transcription factors,NF-�B and activator protein-1 activation [37]. Because astrocytesare supposed to be highly plastic cells potentially modifying theirproperties in primary cultures, it was important to search for thetransduction mechanisms of P2Y1 receptors at astrocytes of ratsin vivo [24]. It was demonstrated that the microinfusion of ADP-�-S (P2Y1,12,13 agonist) into the rat nucleus accumbens or localstab wound injury caused a significant increase in phosphorylated(p)Akt and pERK1/2 (Fig. 4; see also Section 5). The preferen-tial P2Y1 receptor antagonist PPADS abolished the up-regulationof pAkt. Multiple immunofluorescence labelling indicated a time-dependent expression of pAkt and pMAPK on astrocytes and inaddition their co-localization with P2Y1 receptors [24].

The ATP/UTP sensitive P2Y2 receptors may also have numerouseffects on astrocytes [76,77]. They bind via an RGD (Arg-Gly-Asp) motif in their first extracellular loop to integrins,whereupon the integrin signaling pathways regulate cytoskele-


tal reorganization and cell motility. The C-terminus of the P2Y2receptor contains two Src-homology-3 binding domains that pro-mote association with Src and transactivation of growth factorreceptors.




4 H. Franke, P. Illes / Neuroscience Letters xxx (2013) xxx– xxx

Fig. 2. Pharmacological characterization of P2X7 receptors of astroglial cells in brain slices of the oriens layer of the hippocampus by agonists and antagonists. Whole-cellpatch clamp recording. (A) BzATP or ATP were applied twice in a normal aCSF and subsequently again twice in a low X2+ superfusion medium (low Ca2+/no Mg2+ containingextracellular solution). Representative recording of the ATP effect (Aa) and current amplitudes in response to BzATP and ATP before and after the reduction of divalent cationsin the external medium (Ab). The mean ± S.E.M. of the mean of the second and fourth response to the P2 receptor agonists was evaluated in a series of 4 applications. (B)Current responses to increasing concentrations of BzATP and ATP in a low X2+ extracellular solution. Representative recording of the BzATP effect (Ba). Concentration–responserelationships of BzATP (empty circles) and ATP (empty squares) (Bb; n = 6–8). (C) BzATP or NMDA were applied 6 times, before, during, and after superfusion with the selectiveP2X7 receptor antagonist A 438079. Representative recording of the interaction between A 438079 and BzATP (Ca). Concentration-dependent inhibition of the BzATP effect byA 438079 and interaction of NMDA with the P2X7 receptor antagonist (Cb). Mean ± S.E.M. of the mean of the agonist-induced current in the presence of A 438079 measuredat 15 min, normalized with respect to the current measured at 5 min, after starting the application protocol. *P < 0.05; statistically significant difference from the seconda he nu

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. ATP as a stimulus for astrogliosis

Astrocytes react to endogenous or exogenous ATP with hyper-rophy, swelling of the cell body and main processes, androliferation, that ultimately result in full blown astrogliotic phe-


otype with subsequent formation of the glial scar [25]. In culturedstrocytes, it has repeatedly been shown that extracellular ATP andts structural analogues increase GFAP content and DNA synthesis25,52]. Morphological remodelling e.g. ‘stellation’ or an increase

mber of identical experiments (4–6) are indicated in the columns of Ab and Cb.

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in the mean length of processes of GFAP positive cells was alsodescribed in vitro.

Microglia is one of the identified sources of extracellular ATP inneuroinflammatory conditions; this ATP may act on neighboringastrocytes and neurons [33]. Microglial P2Y6,12 and P2X4,7 recep-


tors may be involved in regulating cellular motility, phagocytosis,apoptosis/necrosis and the release of various kinds of endogenoussubstances [14,58]. Thus, these resident macrophages of the CNS,which constitute the first immunological defence mechanism of the


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Fig. 3. Schematic representation of the pathological role of P2X7 receptors inastroglia. P2X7 receptors activate caspase-1 as an apoptotic enzyme and initiatethe cleavage of pro-interleukin-1� to interleukin-1� (IL-1�). In addition, cytoskele-tal changes occur, leading to membrane blebbing. Both P2X7 receptors themselvesand connexin hemichannels function as exit pathways for glutamate and ATP. P2X7receptor stimulation via the [Ca2+]i-induced transactivation of second-messengerpathways coupled to P2Y receptors causes cell proliferation and inflammation. PLC,phospholipase C; PKC, protein kinase C; PI3K, phosphoinositide 3-kinase; PKB/Akt,protein kinase B/Akt; NF-�B, nuclear factor �B; MAPK, mitogen-activated proteinkinase; ERK 1/2, extracellular signal regulated kinase 1/2; p38, p38 kinase; JNK,c

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rain and spinal cord, are unequivocally one of the key players inhe development of astrogliosis. However, according to the mainurpose of this review we will mostly neglect microglial participa-ion in astrogliosis and refer in this respect to some more generalverviews [10,23,25,68].

Proliferation of reactive astrocytes, as indicated by bromod-oxyuridine (BrdU) incorporation or the expression of Ki67 (aroliferation marker), is stimulated by ATP and P2 receptor agonists

n vivo and in vitro [1]. The total number of astrocytes (identified.g. by GFAP or S100� labelling) increases over time and in corre-ation with the expression of additional nucleotide receptors [21].owever, ATP is only one of many endogenous factors determin-

ng astrogliosis, acting alone or together with cytokines (IL, TNF,nterferons), growth factors (fibroblast growth factor-2, leukaemianhibitory factor), neurotransmitters (glutamate, noradrenaline),eactive oxygen radicals, nitric oxide, etc. [22].

. Acute damage to astrocytes and its chroniconsequences; trauma and ischemia

Immediately after traumatic or ischemic damage to the brain,xtracellular ATP concentrations increase (see below) because ofhe outflow from dying cells, the active release from surviving cells,nd due to lack of efficient metabolism by degrading enzymes [10].ocal cerebral ischemia by intraluminal occlusion of the medialerebral artery (MCAO) led to the release of ATP into the rat stri-tal microdialysate [49]. At the same time, mechanical injury tohe rat nucleus accumbens elevated the concentrations of both ATPnd glutamate in the microdialysate [21]. Weight drop impact tohe spinal cord caused a sustained high ATP release in the per-traumatic area as measured by a bioluminescence method [75].


strocytic hemichannels formed from connexin 30/43 constitutedn important route for post-traumatic ATP release, which aggra-ated secondary injury [14].

PRESSetters xxx (2013) xxx– xxx 5

Because cellular proliferation, being a hallmark of strogliosis, ismediated by ERK1/2, members of the MAPK family, it was hypoth-esized that mechanical trauma would activate ERK in astrocytes[55]. In fact, when astrocytes cultured on deformable membraneswere subjected to rapid, reversible strain (stretch)-induced injury,activation of ERK occurred. ERK activation was inhibited by theapplication of non-selective P2 receptor antagonists. In agreementwith these in vitro findings, immunohistochemical investigations inthe nucleus accumbens of rats showed that after stab wound injurythe normally absent P2Y2,6 receptor-immunoreactivity (IR) becameapparent on astrocytes [19]. Moreover the main astrocytic P2Yreceptor-subtype P2Y1 was massively increased and its expressionwas inhibited by preferential (PPADS) and selective (MRS 2179)antagonists of P2Y1 receptors.

Intracerebral administration of P2Y1 receptor agonists led to anincrease in cerebral infarct volume after transient middle cerebralartery occlusion (MCAO) [44]. The respective antagonist MRS2179counteracted this effect and also depressed the expression of var-ious cytokine receptors at astrocytes by interfering with theirsignaling pathways through NF-�B-activation. The non-selectiveP2X/Y receptor antagonists suramin and PPADS reduced the corticalinfarct volume and accelerated functional recovery in behavioraltests [38,46]. In vivo multiphoton imaging showed that traumaticbrain injury to rats triggered intercellular Ca2+ waves through-out the astrocytes and these waves were mediated by purinergicsignaling [11]. Subsequent in vitro screening demonstrated thatastrocyte signaling through the penumbra affected the activity ofneural circuits distant from the injury epicentre, and a reductionin the intercellular Ca2+ waves within astrocytes restored neuralactivity after injury. In consequence, the P2Y1 receptor antago-nist MRS 2179 improved histological and cognitive outcomes ina preclinical model of traumatic brain injury.

In contrast to the described beneficial effect of P2Y1 receptorantagonists, cytotoxic edema and cerebral infarct induced by sin-gle vessel photothrombolysis could be favorably influenced by theP2Y1 receptor agonist, 2-methylthio ADP (2-MeSADP) [82,83]. Pho-tothrombolysis was accompanied by a loss of GFAP fluorescence, asastrocytes lysed. It was suggested that 2-MeSADP has a protectiveeffect on astrocytes by enhancing their mitochondrial metabolismvia InsP3-dependent Ca2+ release. Similarly, 2-MeSADP via P2Y1receptor activation significantly reduced all post-injury symptomsof mechanical trauma in mice, including edema, neuronal swellingand reactive gliosis [69]. Thus, ADP generated by enzymatic degra-dation of the massively released ATP at the early stage of metabolicor mechanical CNS damage appeared to promote astrogliosis [60],whereas at a later stage this ADP may exert an opposite, protectiveeffect.

Furthermore, in the rat brain, MCAO led to the up-regulationof P2X7 receptor-IR in the penumbra surrounding the necroticregion [20]. This immunoreactivity was co-localized with astrocyticand neuronal markers; immunoelectron microscopy revealed theexpression of P2X7 receptors on presynaptic elements of neuronsand perisynaptic processes of glial cells.

It is well known that microglial cells also possess P2X7 recep-tors. These receptors became activated in a rat model of localcerebral ischemia and participated in the early defence reac-tion [80]. P2X7-IR was predominantly detected in microglia, andthen activated microglia accumulated in the ischemic region inrats subjected to MCAO. Intracerebroventricular injection of Bz-ATP improved, whereas its antagonist oxidized ATP exacerbatedischemic damage. In addition, microglial processes converged onthe site of traumatic injury, thereby establishing a barrier between


late with previous reports that show the presence of P2Y12 andP2Y6 receptors at microglia regulating chemotactic and phagocy-totic activities by ADP and UDP, respectively [30,42]. In addition,




6 H. Franke, P. Illes / Neuroscience Letters xxx (2013) xxx– xxx

Fig. 4. Changes in Akt-phosphorylation after stab wound injury in the nucleus accumbens (NAc) of rats in vivo. (A) Example of Western blot of tissue extracts of the NAc ofrats of the phosphorylation status of Akt at different time points after injury and artificial cerebrospinal fluid (ACSF)-microinjection in comparison with untreated controls(C). (B) Data of densitometrical quantification of the phosphorylated form of Akt (pAkt, as fold increase). (*P < 0.05, vs. uninjured control). (C)–(L) Confocal images of doubleimmunofluorescence of pAkt1/2/3 and GFAP at the different time-points. (C) and (D) Very low pAkt-IR under control conditions, (E) and (F) coexpression of pAkt on astrocytes24 h after injury (thin arrows; overview), and (G) and (H) a small number of pAkt-positive astrocytes, double labelling around blood vessels (stars) and non-GFAP-positivecells (thick arrows) 4 days after injury. Examples of the colocalization of GFAP and pAkt (I) and (J) 2 h after injury and (K) and (L) 4 days after injury in a larger magnification(thin arrow, astrocyte; thick arrow, non-glial cell). Scale bars, 20 �m.

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2Y6 receptors have been reported to induce chemokine expressionn microglia and astrocytes of the injured brain [39]. It is impor-ant to note that the expression of P2X7 receptors, accompanyinghe activation of microglia in the brain after mechanical injury or

etabolic limitation, is an early reaction, followed later by theppearance of these receptors at neuroglial cells and probably alsoeurons [27].

Hence, both mechanical damage and ischemia up-regulated P2Xnd P2Y receptor-IR at astrocytes. This suggests that a high localelease of ATP, e.g. by fostering the integration of P2X/Y recep-


ors into the astrocytic membrane (shown in human P2X7-HEK293ells after oxygen-glucose deficiency; [50]) is determined by thenterplay of the ATP concentration and the up-regulated nucleotideeceptors [10].

6. Chronic damage to astrocytes; neurodegenerativeillnesses, epilepsy, and neuropathic pain

In addition to various traumatic or hypoxic insults, chronicneurodegenerative and demyelinating disorders cause sustainedinflammatory astrogliosis [14]. There is ample evidence thatnucleotides are involved as an adjunct factor aggravating theprogress of Alzheimer’s disease, Parkinson’s disease, Hunting-tons’s disease, multiple sclerosis, and amyotrophic lateral sclerosis[10,65]. It appears that microglial cells are the primary players


contributing to neurodegeneration/neuroinflammation enforcingsecondary damage of neurons and astrocytes [25]. However,there is also a limited amount of data supporting direct involve-ment of astrocytes. For example in Alzheimer’s disease (AD),


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on-amyloidogenic processing of the amyloid precursor proteinAPP) by �-secretases leads to proteolytic cleavage within the �-myloid peptide sequence and shedding of the soluble APP (sAPP�)ctodomain, which has been reported to possess neuroprotectiveroperties [78]. Astrocytes are one of the potential sources of APP;oth ATP via P2X7 and UTP via P2Y2 receptor activation may stimu-

ate the non-amyloidogenic cleavage of APP by �-secretase [13,70].hus, paradoxically, P2X7 but also P2Y2 receptors may be neuro-rotective in AD.

In human multiple sclerosis (MS) lesions of autopsy brain tis-ues, IR for the P2X7 receptor was demonstrated on reactivestrocytes [51]. In cultures of primary human foetal astrocytes,2X7 receptor stimulation increased the production of IL-1�-nduced NO synthase and in consequence fostered neuronalamage, raising the possibility that such a mechanism is involved inhe pathology of MS. In post-mortem samples of the cerebral cortexf MS patients, the P2Y12 receptor was highly enriched in myelinnd intralaminar astrocytes, but absent from protoplasmic astro-ytes residing in the deeper cortical layers [4]. It was concluded thathe loss of P2Y12 receptors might be detrimental to tissue injury.

The temporal lobe epilepsy syndrome can be modelled inodents by chemical induction of status epilepticus using kanater pilocarpine [17]. Complex partial seizures and status epilepticusan cause hippocampal neuronal death, mossy fibre sprout-ng, gliosis, and molecular reorganization of membrane proteins.fter chemically-induced epilepsy in rodents, the P2X7-IR is up-egulated in neurons and microglia, paralleled by astroglial loss36,40]. Treatment with selective P2X7 receptor antagonists wererotective against epileptic seizures and counteracted astroglial

oss. At the moment it is likely that the damage to astrocytes isostly a consequence of microglial activation.Neuropathic pain is a common and severely disabling state

hat can be experienced after nerve injury or as a part of dis-ases affecting peripheral nerve function such as diabetes or AIDS10]. Although microglial P2X4 receptors were described to berimarily involved in this state [71], astrocyte-like satellite cells

ocated in sensory ganglia may also play major roles. Thus, it wasuggested that P2X7 receptors located at satellite cells are tar-ets of ATP released from dorsal root ganglion (DRG) neurons,hich in consequence release themselves TNF-� to potentiate P2X3

eceptor-mediated responses at nearby neurons [81]. P2X3 recep-ors at the central terminals of DRG neurons are well known toegulate pain sensation. Thus, neurons and surrounding glial cellsn the sensory ganglia communicate with each other via signaling

olecules; this communication has implications for the manifes-ation of chronic pain [28].

. Conclusions

Astroglia are a highly heterogenous class of neural cells thatrovide a homeostatic system of the brain and spinal cord. Astrogliaontrol the blood brain barrier, shape the microarchitecture ofhe brain, support synaptogenesis, supply neurons with energyubstrate, and regulate concentrations of ions, neurotransmittersnd neurohormones [32]. Furthermore, astrocytes (together withicroglia) represent a defence system of the CNS; disturbance

f neural tissue triggers evolutionarily conserved programs ofstrogliosis. Traumatic injury and ischemic/haemorrhagic strokeause massive, immediate release of ATP from neural and non-eural cells in the damaged tissue. While in the core of the lesion,eurons and astrocytes are usually irreversibly damaged and in


onsequence die, in the penumbra around the core, ATP, by actingt certain P2X and P2Y receptors induce secondary astroglio-is. Chronic neurodegenerative illnesses, epilepsy and neuropathicain develop slowly, and are accompanied by neuroinflammation,

[

[


leading to astrogliosis. P2X and P2Y receptors have a wide distribu-tion in the CNS, often exerting opposing effects according to theirlocalization (e.g. microglia vs. astrocytes) or the time-window oftheir activation (early vs. late effects). However, in the majorityof the experimental studies, the deleterious effects of endogenousATP/ADP appeared to predominate over the favorable ones, andtherefore pharmacological antagonists of P2X/P2Y receptors ame-liorated the long-lasting consequences of any type of CNS injury.Thus, the use of such drugs may open new vistas for therapeuticapplication in humans.

References

[1] M.P. Abbracchio, M.J. Saffrey, V. Hopker, G. Burnstock, Modulation of astroglialcell proliferation by analogues of adenosine and ATP in primary cultures of ratstriatum, Neuroscience 59 (1994) 67–76.

[2] M.P. Abbracchio, G. Burnstock, J.M. Boeynaems, E.A. Barnard, J.L. Boyer, C.Kennedy, G.E. Knight, M. Fumagalli, C. Gachet, K.A. Jacobson, G.A. Weis-man, International union of pharmacology LVIII: update on the P2Y Gprotein-coupled nucleotide receptors: from molecular mechanisms and patho-physiology to therapy, Pharmacol. Rev. 58 (2006) 281–341.

[3] M.P. Abbracchio, G. Burnstock, A. Verkhratsky, H. Zimmermann, Purinergicsignaling in the nervous system: an overview, Trends Neurosci. 32 (2009)19–29.

[4] S. Amadio, C. Montilli, R. Magliozzi, G. Bernardi, R. Reynolds, C. Volonte, P2Y12

receptor protein in cortical gray matter lesions in multiple sclerosis, Cereb.Cortex 20 (2010) 1263–1273.

[5] A. Araque, V. Parpura, R.P. Sanzgiri, P.G. Haydon, Tripartite synapses: glia, theunacknowledged partner, Trends Neurosci. 22 (1999) 208–215.

[6] D. Boison, Adenosine dysfunction in epilepsy, Glia 60 (2012) 1234–1243.[7] R. Brambilla, J.T. Neary, F. Cattabeni, L. Cottini, G. D’Ippolito, P.C. Schiller, M.P.

Abbracchio, Induction of COX-2 and reactive gliosis by P2Y receptors in rat cor-tical astrocytes is dependent on ERK1/2 but independent of calcium signaling,J. Neurochem. 83 (2002) 1285–1296.

[8] R. Brambilla, L. Cottini, M. Fumagalli, S. Ceruti, M.P. Abbracchio, Blockade of A2Aadenosine receptors prevents basic fibroblast growth factor-induced reactiveastrogliosis in rat striatal primary astrocytes, Glia 43 (2003) 190–194.

[9] G. Burnstock, Cotransmission, Curr. Opin. Pharmacol. 4 (2004) 47–52.10] G. Burnstock, U. Krugel, M.P. Abbracchio, P. Illes, Purinergic signaling: from

normal behaviur to pathological brain function, Prog. Neurobiol. 95 (2011)229–274.

11] A.M. Choo, W.J. Miller, Y.C. Chen, P. Nibley, T.P. Patel, C. Goletiani, B. Morrison,M.K. Kutzing, B.L. Firestein, J.Y. Sul, P.G. Haydon, D.F. Meaney, Antagonism ofpurinergic signaling improves recovery from traumatic brain injury, Brain 136(2013) 65–80.

12] D. Davalos, J. Grutzendler, G. Yang, J.V. Kim, Y. Zuo, S. Jung, D.R. Littman, M.L.Dustin, W.B. Gan, ATP mediates rapid microglial response to local brain injuryin vivo, Nat. Neurosci. 8 (2005) 752–758.

13] C. Delarasse, R. Auger, P. Gonnord, B. Fontaine, J.M. Kanellopoulos, The puriner-gic receptor P2X7 triggers �-secretase-dependent processing of the amyloidprecursor protein, J. Biol. Chem. 286 (2011) 2596–2606.

14] V.F. Di Virgilio, S. Ceruti, P. Bramanti, M.P. Abbracchio, Purinergic signaling ininflammation of the central nervous system, Trends Neurosci. 32 (2009) 79–87.

15] S. Duan, C.M. Anderson, E.C. Keung, Y. Chen, Y. Chen, R.A. Swanson, P2X7receptor-mediated release of excitatory amino acids from astrocytes, J. Neu-rosci. 23 (2003) 1320–1328.

16] I. Dusart, M.E. Schwab, Secondary cell death and the inflammatory reactionafter dorsal hemisection of the rat spinal cord, Eur. J. Neurosci. 6 (1994)712–724.

17] T. Engel, A. Jimenez-Pacheco, M.T. Miras-Portugal, M. Diaz-Hernandez, D.C.Henshall, P2X7 receptor in epilepsy; role in pathophysiology and potential tar-geting for seizure control, Int. J. Physiol. Pathophysiol. Pharmacol. 4 (2012)174–187.

18] W. Fischer, K. Appelt, M. Grohmann, H. Franke, W. Norenberg, P. Illes, Increaseof intracellular Ca2+ by P2X and P2Y receptor-subtypes in cultured corticalastroglia of the rat, Neuroscience 160 (2009) 767–783.

19] H. Franke, U. Krugel, J. Grosche, C. Heine, W. Hartig, C. Allgaier, P. Illes, P2Y recep-tor expression on astrocytes in the nucleus accumbens of rats, Neuroscience127 (2004) 431–441.

20] H. Franke, A. Gunther, J. Grosche, R. Schmidt, S. Rossner, R. Reinhardt, H. Faber-Zuschratter, D. Schneider, P. Illes, P2X7 receptor expression after ischemia inthe cerebral cortex of rats, J. Neuropathol. Exp. Neurol. 63 (2004) 686–699.

21] H. Franke, B. Grummich, W. Hartig, J. Grosche, R. Regenthal, R.H. Edwards, P.Illes, U. Krugel, Changes in purinergic signaling after cerebral injury – involve-ment of glutamatergic mechanisms? Int. J. Dev. Neurosci. 24 (2006) 123–132.

22] H. Franke, P. Illes, Involvement of P2 receptors in the growth and survival ofneurons in the CNS, Pharmacol. Ther. 109 (2006) 297–324.


23] H. Franke, C. Schepper, P. Illes, U. Krugel, Involvement of P2X and P2Y receptorsin microglial activation in vivo, Purinergic Signal. 3 (2007) 435–445.

24] H. Franke, C. Sauer, C. Rudolph, U. Krugel, J.G. Hengstler, P. Illes, P2 receptor-mediated stimulation of the PI3-K/Akt-pathway in vivo, Glia 57 (2009)1031–1045.


http://refhub.elsevier.com/S0304-3940(13)00880-X/sbref0005






















































































































































































































































































































































































































































































































































































































































































































































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25] H. Franke, A. Verkhratsky, G. Burnstock, P. Illes, Pathophysiology of astroglialpurinergic signaling, Purinergic Signal. 8 (2012) 629–657.

26] H. Franke, C. Parravicini, D. Lecca, E.R. Zanier, C. Heine, K. Bremicker, M.Fumagalli, P. Rosa, L. Longhi, N. Stocchetti, M.G. De Simoni, M. Weber, M.P.Abbracchio, Changes of the GPR17 receptor, a new target for neurorepair, inneurons and glial cells in patients with traumatic brain injury, Purinergic Signal.9 (2013) 451–462.

27] C.J. Gallagher, M.W. Salter, Differential properties of astrocyte calcium wavesmediated by P2Y1 and P2Y2 receptors, J. Neurosci. 23 (2003) 6728–6739.

28] R.D. Gosselin, M.R. Suter, R.R. Ji, I. Decosterd, Glial cells and chronic pain, Neu-roscientist 16 (2010) 519–531.

29] P.B. Guthrie, J. Knappenberger, M. Segal, M.V. Bennett, A.C. Charles, S.B. Kater,ATP released from astrocytes mediates glial calcium waves, J. Neurosci. 19(1999) 520–528.

30] S. Honda, Y. Sasaki, K. Ohsawa, Y. Imai, Y. Nakamura, K. Inoue, S. Kohsaka,Extracellular ATP or ADP induce chemotaxis of cultured microglia throughGi/o-coupled P2Y receptors, J. Neurosci. 21 (2001) 1975–1982.

31] P. Illes, J. Alexandre Ribeiro, Molecular physiology of P2 receptors in the centralnervous system, Eur. J. Pharmacol. 483 (2004) 5–17.

32] P. Illes, A. Verkhratsky, G. Burnstock, H. Franke, P2X receptors and their rolesin astroglia in the central and peripheral nervous system, Neuroscientist 18(2012) 422–438.

33] Y. Imura, Y. Morizawa, R. Komatsu, K. Shibata, Y. Shinozaki, H. Kasai, K. Moriishi,Y. Moriyama, S. Koizumi, Microglia release ATP by exocytosis, Glia 61 (2013)1320–1330.

34] R. Jabs, K. Matthias, A. Grote, M. Grauer, G. Seifert, C. Steinhauser, Lack ofP2X receptor mediated currents in astrocytes and GluR type glial cells of thehippocampal CA1 region, Glia 55 (2007) 1648–1655.

35] G. James, A.M. Butt, P2Y, P2X purinoceptor mediated Ca2+ signaling in glial cellpathology in the central nervous system, Eur. J. Pharmacol. 447 (2002) 247–260.

36] A. Jimenez-Pacheco, G. Mesuret, A. Sanz-Rodriguez, K. Tanaka, C. Mooney,R. Conroy, M.T. Miras-Portugal, M. Diaz-Hernandez, D.C. Henshall, T. Engel,Increased neocortical expression of the P2X7 receptor after status epilepticusand anticonvulsant effect of P2X7 receptor antagonist A-438079, Epilepsia 54(2013) 1551–1561.

37] G.R. John, J.E. Simpson, M.N. Woodroofe, S.C. Lee, C.F. Brosnan, Extracellularnucleotides differentially regulate interleukin-1� signaling in primary humanastrocytes: implications for inflammatory gene expression, J. Neurosci. 21(2001) 4134–4142.

38] A. Kharlamov, S.C. Jones, D.K. Kim, Suramin reduces infarct volume in a modelof focal brain ischemia in rats, Exp. Brain Res. 147 (2002) 353–359.

39] B. Kim, H.K. Jeong, J.H. Kim, S.Y. Lee, I. Jou, E.H. Joe, Uridine 5′-diphosphateinduces chemokine expression in microglia and astrocytes through activationof the P2Y6 receptor, J. Immunol. 186 (2011) 3701–3709.

40] J.E. Kim, S.E. Kwak, S.M. Jo, T.C. Kang, Blockade of P2X receptor preventsastroglial death in the dentate gyrus following pilocarpine-induced statusepilepticus, Neurol. Res. 31 (2009) 982–988.

41] S. Koizumi, K. Fujishita, M. Tsuda, Y. Shigemoto-Mogami, K. Inoue,Dynamic inhibition of excitatory synaptic transmission by astrocyte-derivedATP in hippocampal cultures, Proc. Natl. Acad. Sci. U.S.A. 100 (2003)11023–11028.

42] S. Koizumi, K. Ohsawa, K. Inoue, S. Kohsaka, Purinergic receptors in microglia:functional modal shifts of microglia mediated by P2 and P1 receptors, Glia 61(2013) 47–54.

43] L. Koles, A. Leichsenring, P. Rubini, P. Illes, P2 receptor signaling in neurons andglial cells of the central nervous system, Adv. Pharmacol. 61 (2011) 441–493.

44] K. Kuboyama, H. Harada, H. Tozaki-Saitoh, M. Tsuda, K. Ushijima, K. Inoue,Astrocytic P2Y1 receptor is involved in the regulation of cytokine/chemokinetranscription and cerebral damage in a rat model of cerebral ischemia, J. Cereb.Blood Flow Metab. 31 (2011) 1930–1941.

45] U. Lalo, Y. Pankratov, S.P. Wichert, M.J. Rossner, R.A. North, F. Kirch-hoff, A. Verkhratsky, P2X1 and P2X5 subunits form the functionalP2X receptor in mouse cortical astrocytes, J. Neurosci. 28 (2008)5473–5480.

46] A.B. Lammer, A. Beck, B. Grummich, A. Forschler, T. Krugel, T. Kahn, D. Schnei-der, P. Illes, H. Franke, U. Krugel, The P2 receptor antagonist PPADS supportsrecovery from experimental stroke in vivo, PLoS ONE 6 (2011) e19983.

47] W. Ma, H. Hui, P. Pelegrin, A. Surprenant, Pharmacological characterization ofpannexin-1 currents expressed in mammalian cells, J. Pharmacol. Exp. Ther.328 (2009) 409–418.

48] J. McGraw, G.W. Hiebert, J.D. Steeves, Modulating astrogliosis after neuro-trauma, J. Neurosci. Res. 63 (2001) 109–115.

49] A. Melani, D. Turchi, M.G. Vannucchi, S. Cipriani, M. Gianfriddo, F. Pedata, ATPextracellular concentrations are increased in the rat striatum during in vivoischemia, Neurochem. Int. 47 (2005) 442–448.

50] D. Milius, H. Groger-Arndt, D. Stanchev, C. Lange-Dohna, S. Rossner, B. Sper-lagh, K. Wirkner, P. Illes, Oxygen/glucose deprivation increases the integrationof recombinant P2X7 receptors into the plasma membrane of HEK293 cells,Toxicology 238 (2007) 60–69.

51] L. Narcisse, E. Scemes, Y. Zhao, S.C. Lee, C.F. Brosnan, The cytokine IL-1� tran-siently enhances P2X7 receptor expression and function in human astrocytes,


Glia 49 (2005) 245–258.52] J.T. Neary, L. Baker, S.L. Jorgensen, M.D. Norenberg, Extracellular ATP induces

stellation and increases glial fibrillary acidic protein content and DNA synthesisin primary astrocyte cultures, Acta Neuropathol. 87 (1994) 8–13.

[

PRESSLetters xxx (2013) xxx– xxx

53] J.T. Neary, M.P. Rathbone, F. Cattabeni, M.P. Abbracchio, G. Burnstock, Trophicactions of extracellular nucleotides and nucleosides on glial and neuronal cells,Trends Neurosci. 19 (1996) 13–18.

54] J.T. Neary, Y. Kang, Y. Bu, E. Yu, K. Akong, C.M. Peters, Mitogenicsignaling by ATP/P2Y purinergic receptors in astrocytes: involvement of acalcium-independent protein kinase C, extracellular signal-regulated proteinkinase pathway distinct from the phosphatidylinositol-specific phospholipaseC/calcium pathway, J. Neurosci. 19 (1999) 4211–4220.

55] J.T. Neary, Y. Kang, K.A. Willoughby, E.F. Ellis, Activation of extracellular signal-regulated kinase by stretch-induced injury in astrocytes involves extracellularATP and P2 purinergic receptors, J. Neurosci. 23 (2003) 2348–2356.

56] W. Norenberg, P. Illes, Neuronal P2X receptors: localisation and functionalproperties, Naunyn Schmiedebergs Arch. Pharmacol. 362 (2000) 324–339.

57] W. Norenberg, J. Schunk, W. Fischer, H. Sobottka, T. Riedel, J.F. Oliveira,H. Franke, P. Illes, Electrophysiological classification of P2X7 recep-tors in rat cultured neocortical astroglia, Br. J. Pharmacol. 160 (2010)1941–1952.

58] K. Ohsawa, S. Kohsaka, Dynamic motility of microglia: purinergic modulationof microglial movement in the normal and pathological brain, Glia 59 (2011)1793–1799.

59] J.F. Oliveira, T. Riedel, A. Leichsenring, C. Heine, H. Franke, U. Krugel, W.Norenberg, P. Illes, Rodent cortical astroglia express in situ functional P2X7receptors sensing pathologically high ATP concentrations, Cereb. Cortex 21(2011) 806–820.

60] C. Quintas, S. Fraga, J. Goncalves, G. Queiroz, Opposite modulation ofastroglial proliferation by adenosine 5′-O-(2-thio)-diphosphate and 2-methylthioadenosine-5′-diphosphate: mechanisms involved, Neuroscience182 (2011) 32–42.

61] J.L. Ridet, S.K. Malhotra, A. Privat, F.H. Gage, Reactive astrocytes: cellu-lar and molecular cues to biological function, Trends Neurosci. 20 (1997)570–577.

62] S.C. Robson, J. Sevigny, H. Zimmermann, The E-NTPDase family of ectonucle-otidases: structure function relationships and pathophysiological significance,Purinergic Signal. 2 (2006) 409–430.

63] S. Roger, P. Pelegrin, A. Surprenant, Facilitation of P2X7 receptor currents andmembrane blebbing via constitutive and dynamic calmodulin binding, J. Neu-rosci. 28 (2008) 6393–6401.

64] A. Rolls, R. Shechter, M. Schwartz, The bright side of the glial scar in CNS repair,Nat. Rev. Neurosci. 10 (2009) 235–241.

65] S.D. Skaper, P. Debetto, P. Giusti, The P2X7 purinergic receptor: from physiologyto neurological disorders, FASEB J. 24 (2010) 337–345.

66] M.V. Sofroniew, Molecular dissection of reactive astrogliosis and glial scar for-mation, Trends Neurosci. 32 (2009) 638–647.

67] B. Sperlagh, E.S. Vizi, K. Wirkner, P. Illes, P2X7 receptors in the nervous system,Prog. Neurobiol. 78 (2006) 327–346.

68] B. Sperlagh, P. Illes, Purinergic modulation of microglial cell activation, Puriner-gic Signal. 3 (2007) 117–127.

69] W.L. Talley, S. Sprague, W. Zheng, R.J. Garling, D. Jimenez, M. Digicaylioglu, J.Lechleiter, Purinergic 2Y1 receptor stimulation decreases cerebral edema andreactive gliosis in a traumatic brain injury model, J. Neurotrauma 30 (2013)55–66.

70] M.D. Tran, P2 receptor stimulation induces amyloid precursor protein produc-tion and secretion in rat cortical astrocytes, Neurosci. Lett. 492 (2011) 155–159.

71] M. Tsuda, H. Tozaki-Saitoh, K. Inoue, Pain and purinergic signaling, Brain Res.Rev. 63 (2010) 222–232.

72] A. Verkhratsky, R.K. Orkand, H. Kettenmann, Glial calcium: homeostasis andsignaling function, Physiol. Rev. 78 (1998) 99–141.

73] A. Verkhratsky, O.A. Krishtal, G. Burnstock, Purinoceptors on neuroglia, Mol.Neurobiol. 39 (2009) 190–208.

74] A. Verkhratsky, M.V. Sofroniew, A. Messing, N.C. deLanerolle, D. Rempe, J.J.Rodriguez, M. Nedergaard, Neurological diseases as primary gliopathies: areassessment of neurocentrism, ASN Neuro 4 (2012) e00082.

75] X. Wang, G. Arcuino, T. Takano, J. Lin, W.G. Peng, P. Wan, P. Li, Q. Xu, Q.S. Liu,S.A. Goldman, M. Nedergaard, P2X7 receptor inhibition improves recovery afterspinal cord injury, Nat. Med. 10 (2004) 821–827.

76] G.A. Weisman, M. Wang, Q. Kong, N.E. Chorna, J.T. Neary, G.Y. Sun, F.A. Gonzalez,C.I. Seye, L. Erb, Molecular determinants of P2Y2 nucleotide receptor function:implications for proliferative and inflammatory pathways in astrocytes, Mol.Neurobiol. 31 (2005) 169–183.

77] G.A. Weisman, J.M. Camden, T.S. Peterson, D. Ajit, L.T. Woods, L. Erb, P2 receptorsfor extracellular nucleotides in the central nervous system: role of P2X7 andP2Y2 receptor interactions in neuroinflammation, Mol. Neurobiol. 46 (2012)96–113.

78] V. Wilquet, S.B. De Strooper, Amyloid-� precursor protein processing in neu-rodegeneration, Curr. Opin. Neurobiol. 14 (2004) 582–588.

79] K. Wirkner, A. Gunther, M. Weber, S.J. Guzman, T. Krause, J. Fuchs, L. Koles, W.Norenberg, P. Illes, Modulation of NMDA receptor current in layer V pyramidalneurons of the rat prefrontal cortex by P2Y receptor activation, Cereb. Cortex17 (2007) 621–631.

80] D. Yanagisawa, Y. Kitamura, K. Takata, I. Hide, Y. Nakata, T. Taniguchi, Possibleinvolvement of P2X7 receptor activation in microglial neuroprotection against


focal cerebral ischemia in rats, Biol. Pharm. Bull. 31 (2008) 1121–1130.81] X. Zhang, Y. Chen, C. Wang, L.Y. Huang, Neuronal somatic ATP release trigg-

ers neuron-satellite glial cell communication in dorsal root ganglia, Proc. Natl.Acad. Sci. U.S.A. 104 (2007) 9864–9869.


















































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































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and partially reverses ischemic neuronal damage in mouse, J. Cereb. Blood Flow



82] W. Zheng, L.T. Watts, D.M. Holstein, S.I. Prajapati, C. Keller, E.H. Grass, C.A. Wal-


ter, J.D. Lechleiter, Purinergic receptor stimulation reduces cytotoxic edemaand brain infarcts in mouse induced by photothrombosis by energizing glialmitochondria, PLoS ONE 5 (2010) e14401.

83] W. Zheng, W.L. Talley, D.M. Holstein, J. Wewer, J.D. Lechleiter, P2Y1R-initiated,IP3R-dependent stimulation of astrocyte mitochondrial metabolism reduces

[



Metab. 33 (2013) 600–611.84] H. Zimmermann, M. Zebisch, N. Strater, Cellular function and molec-

ular structure of ecto-nucleotidases, Purinergic Signal. 8 (2012)437–502.





































































































Nucleotide signaling in astrogliosis

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