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MINIREVIEWPost-ischemic brain damage: targeting PARP-1 within theischemic neurovascular units as a realistic avenue tostroke treatmentFlavio Moroni and Alberto ChiarugiDepartment of Preclinical and Clinical Pharmacology, University of Florence, ItalyTherapeutic strategies aimed at reducing brain dam-age after ischemic stroke have been a major focus ofacademic and industrial research for the past30 years. Two primary therapeutic approaches havebeen intensively studied: the first can be defined asthe ‘vascular approach’ and its main goal is the rapidre-opening of occluded blood vessels so that oxygenand nutrients may return to the ischemic region. Thesecond may be defined as the ‘cellular approach’ andis based on the possibility of interfering with the sig-naling pathways, leading to loss of neurons and dam-age of other cellular elements present in the affectedbrain region [1,2]. Efforts directed at developing effec-tive vascular therapy led to clinically usefulprocedures and have clearly demonstrated that it ispossible to reduce, selectively, brain damage andneurologic disability by administering recombinant tis-sue plasminogen activator within 3 h from when thestroke symptoms first start. Conversely, the cellularapproach has been so far clinically unsuccessful, andnone of the numerous neuroprotective strategies thathave been tested in clinical trials have reached theclinical arena [3,4].Exciting, radical, suicidal andinflamed – the many pathways ofischemic brain injuryThe enormous body of information on ischemic neuro-degeneration in different experimental stroke modelshas shed light on the complex signaling pathways andmolecular events responsible for neuronal damageKeywordsblood brain barrier; endothelium;inflammation; ischemia; microglia;neuroprotection; neurovascular unit;PARP-1; pericytes; strokeCorrespondenceF. Moroni, Dipartimento di Farmacologia,Viale Pieraccini 6, 50139 Firenze, ItalyFax: +39 055 4271226Tel: +39 055 4271280E-mail: flavio.moroni@unifi.it(Received 3 July 2008, revised 11September 2008, accepted 14 October2008)doi:10.1111/j.1742-4658.2008.06768.xStroke is the third leading cause of death in industrialized countries butefficacious stroke treatment is still an unmet need. Preclinical research indi-cates that different molecules afford protection from ischemic neurodegen-eration, but all clinical trials conducted so far have inexorably failed.Critical re-evaluation of experimental data shows that all the componentsof the neurovascular unit, such as neurons, glia, endothelia and basal mem-branes, must be protected during the ischemic insult to obtain substantialand long-lasting neuroprotection. Here, we propose the nuclear enzymepoly(ADP-ribose) polymerase (PARP-1) as a key effector of cell death inthe various elements of the neurovascular units, and assert that drugsinhibiting PARP-1 may therefore represent valuable tools for pharmacolog-ical treatment of stroke patients.AbbreviationsAIF, apoptosis-inducing factor; BBB, blood–brain barrier; HMGB1, high-mobility-group protein box 1; IL, interleukin; MMP, matrixmetalloproteinase; NMDA, N-methyl-D-aspartate; PARG, poly(ADP-ribose) glycohydrolase; PARP, poly(ADP-ribose) polymerase; PARP-1,poly(ADP-ribose) polymerase 1; ROS, reactive oxygen species; TNF-a, tumor necrosis factor-a.36 FEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBSwhen blood flow to a brain region drops below a criti-cal threshold and when it returns because of vesselre-opening and tissue reperfusion. In the past, particu-lar attention was directed to derangement of excitatoryamino acid-mediated neurotransmission that became,for years, the main target for neuroprotection.Hypoxia ⁄ ischemia increases the concentrations ofextracellular glutamate [5,6] with excessive stimulationof ionotropic and metabotropic glutamate receptors,which initiates a chain of events leading to excitotoxicneuronal death [7,8]. This concept is strongly sup-ported by the observation that, in a number of in vitroand in vivo experimental models of ischemia, glutamatereceptor antagonists, acting either on ionotropic[N-methyl-d-aspartate (NMDA) or Gk alpha-amino-3-hydroxy-5-methyl-4-isoxazolone propinate] or on groupI metabotropic receptors, are effective neuroprotectiveagents [9–13]. Unfortunately, however, none of theglutamate receptor antagonists tested in clinical trialsshowed positive results or had an acceptable benefit ⁄side effects ratio.Triggered by the excitotoxic events as well as byimpairment of mitochondrial respiration, a burst ofreactive oxygen species (ROS) and reactive nitrogenspecies typically occurs within the ischemic brain tis-sue. Again, inhibition of radical formation as well asof radical scavengers provides significant neuroprotec-tion in animal stroke models. Agents acting as free-radical scavengers therefore have been repeatedlyproposed as useful drugs for stroke therapy, but mostwere rapidly discarded because of cardiovascular toxic-ity. Recently, however, the spin-trap nitrone NXY-059from AstraZeneca reached the clinical arena with somesuccess [14]. The putative neuroprotectant is probablyn-t-butyl hydroxylamine and ⁄ or its parent spin-trap2-methyl-2-nitrosopropane, produced by hydrolysis ofNXY-059. Unfortunately, the positive outcome of thefirst clinical trial was not confirmed in a second clinicaltrial, and NXY-059 development was dropped, leavingwidespread scepticism in the field regarding the possi-bility of obtaining ischemic neuroprotection in humans[15].Apoptotic mechanisms also contribute to ischemicneuronal demise. This suicidal form of neurodegenera-tion seems to occur mainly in specific types of brainischemia, including the global type of brain ischemia.Also, activation of the apoptotic program typicallyoccurs in a delayed manner in brain regions present inthe surroundings of the ischemic core (the so-called‘penumbra’, see below) and is thought to be a key com-ponent of time-dependent brain infarct evolution [1].Yet, strategies aimed at inhibiting the several apoptoticeffectors have not been exploited at the clinical level.Another event widely recognized to be of key patho-genetic relevance to post-ischemic brain damage isimmune activation of resident glial cells and leukocytesinfiltrating from blood vessels [16,17]. In this regard,several therapeutic approaches aimed at counteractingpost-ischemic immune activation and infiltration havebeen tested in clinical trials. Some, such as the anti-leu-kocyte adhesion molecules enlimonab and HU23F2G,proved inefficacious and harmful, respectively. Others,such as the interleukin (IL)-1 receptor antagonist, pro-vided inconclusive results. Failure might be a result ofthe fact that both protective as well as detrimentaleffects of the inflammatory response during ischemicneurodegeneration have been reported [18].Critical re-evaluation of drugdevelopment in strokePreclinical studies clearly show that it is feasible toprotect the brain from ischemic injury by means ofpharmacological or genetic approaches aimed at tar-geting the molecular mechanisms involved in ischemicneurodegeneration. Hence, because there are no appar-ent reasons why these strategies should not be effectivein humans, it is reasonable to predict that effectiveneuroprotective strategies identified at the preclinicallevel also reach clinical practice. Then, the question iswhy has this not yet happened? An increasing body ofliterature is accumulating on this subject, and severalcritical points that have been identified are the pastand, unfortunately, present criteria and methodologiesused for drug development in the stroke field [3,4,19].To summarize, it is now clear that animal modelsshould closely reproduce the complex cardiovascularand cerebral pathophysiology of stroke patients, andneuroprotection should be evaluated on a long-lastingand functional basis, rather than on an acute and his-tological basis. Also, careful and rigorous selection ofpatients with salvageable tissue [evidenced using mag-netic resonance imaging as the presence of an area ofhypoperfusion larger than that of altered water diffu-sion (the latter is an index of necrosis), the so-called‘Perfusion ⁄ Diffusion (PWI ⁄ DWI) mismatch’] shouldbe conducted before treating them with an anti-strokedrug candidate [4]. Finally, the concepts of ‘pleiotypicdrugs’ (i.e. drugs with several mechanisms of action)and ‘synergistic combinatorial drug therapy’ emerge askey requisites for efficacious stroke treatment [4].Indeed, one of the possible reasons for the lack of clin-ical efficacy of drugs tested in clinical trials for brainischemia is their selective mechanism of action. Forinstance, glutamate antagonists act exclusively (or pre-dominantly) on neurons. So, even if neurons are theF. Moroni and A. Chiarugi PARP-1 and the ischemic neurovascular unitFEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBS 37first cell type to lose their function when blood supplyis insufficient, the other cell types present in the ner-vous tissue are of the utmost importance to supportneuronal functioning. When capillaries and glia aredamaged, neurons cannot survive in spite of protectionfrom excitotoxic insults. Similarly, selective blocking ofapoptosis or inflammation within the ischemic tissuecannot provide protection when the other detrimentalevents are unrestricted. As a whole, efficacious stroketreatment needs concomitant targeting of the variouspathogenetic events actively contributing to neurode-generation in cells localized within the ischemicpenumbra.Penumbra and the neurovascular unitThe ischemic brain region may be divided into a zonein which blood flow is completely absent (‘ischemiccore’) and a peripheral zone in which collateral ves-sels supply only a fraction of the oxygen and glucoserequired for the normal activity of neural cells (‘ische-mic penumbra’) [2,20]. While all cell types in the coreregion undergo typical necrotic features and die form-ing an infarct zone, the ischemic penumbra mayinitially retain its morphological integrity, even if itsfunctions (i.e. electrical activity, synthetic processes,bioenergetic functions, etc.) are temporally lost. How-ever, if sufficient blood flow eventually returns to theischemic region within a reasonable time (hours) it ispossible to rescue this area, thus limiting the neuro-logical damage. It is now clear that in order toobtain full functional recovery, not only neurons, butall cell types (i.e. astrocytes, microglia, oligodendro-cytes, endothelial cells, muscle cells, pericytes) andstructures (mainly basal membranes) present in the‘penumbra area’ should be rescued [21,22]. Thus,ischemic neuroprotection can be achieved only if theclassic, oversimplified strategy ‘save the neurons’ ischanged into ‘save neural and stromal cells’. Overall,neural and stromal cells are grouped into a functionalentity: the so-called ‘neurovascular unit’. Operatively,the latter is a very complex network of functionsbrought about by different cells and aimed at main-taining the homeostatic milieu necessary for normalbrain activities. Protection of the components of theneurovascular unit seems therefore essential to reducebrain damage and neurological deficits after a stroke.To achieve this, different strategies have been pro-posed and evaluated in preclinical settings. Yet, con-comitant targeting of all the components of theneurovascular units adds substantial complexity tothe feasibility of obtaining ischemic neuroprotectionby pharmacological approaches and, as mentionedabove, general scepticism permeated the field. Asoutlined below, we claim that poly(ADP-ribose) poly-merase 1 (PARP-1) inhibitors are among the mostefficacious protectants of the neurovascular unitcurrently available.PARP-1 activation and cell death in theneurovascular unitPoly(ADP-ribose) polymerases (PARPs) are NAD-dependent enzymes that are able to catalyse the trans-fer of ADP-ribose units from NAD to substrateproteins, thereby contributing to the control of geno-mic integrity, cell cycle and gene expression [23].Among PARPs, nuclear PARP-1 is a DNA damage-activated enzyme of 113 kDa molecular mass and isthe most abundant and commonly studied member ofthe family. Its enzymatic activity leads to poly(ADPribose) formation, and it was first described over40 years ago in liver cell nuclei incubated with NADand ATP in Paul Mandel’s laboratory in Strasburg[24]. Although this seminal observation was made in aneuroscience laboratory, for the following 30 years,research on PARP-1 was exclusively carried out byresearchers mainly involved in genome stability, DNArepair and cancer. The neuroscience communityignored PARP-1 until the early 1990s when it wasshown that it mediates glutamate-induced and nitricoxide-induced neuronal death [25,26]. Excellent workcarried out in the following years uncovered severalmolecular events causally linking PARP-1 activation toischemic cell death [27]. As for the triggers of PARP-1hyperactivity during ischemia, ROS-dependent DNAdamage is thought to play a major role. However,Ca2+-dependent and kinase-dependent PARP-1 activa-tion might also contribute [28–30]. Ambiguity alsoexists regarding the molecular mechanisms underlyingthe detrimental role of the enzyme in ischemic braininjury [31,32]. Indeed, although we know in part themechanisms activated by PARP-1 and triggeringneurotoxicity, which of these is causally involved inPARP-1-dependent ischemic neurodegeneration stillneeds to be elucidated.Experimental data demonstrate that, upon differentstresses, activation of PARP-1 can exert detrimentaleffects in every cell type of the neurovascular unit(Fig. 1). Given that the ischemic challenge mimicsthese stresses, we reason that during brain ischemiaPARP-1-dependent cytotoxicity occurs in all the com-ponents of the neurovascular unit. It is obvious thattriggers, time courses and final effects of PARP-1activation in endothelial, muscle and glial cells, as wellas in infiltrating leukocytes, are different from thosePARP-1 and the ischemic neurovascular unit F. Moroni and A. Chiarugi38 FEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBSoccurring in neurons. Regardless, the hyperactivationof PARP-1 in each single component of the neurovas-cular unit triggers dysfunction ⁄ cytotoxicity and, indi-rectly, severely affects the functioning of neighbouringneurons. As a whole, PARP-1-dependent derangementof the integrity of the neurovascular unit is caused bythe enzyme’s ability to prompt an increase of blood–brain barrier (BBB) permeability, the release of pro-inflammatory mediators, mitochondrial dysfunctionand bioenergetic failure, as well as the activation ofspecific apoptotic pathways.PARP-1, endothelia and post-ischemicBBB breakdownIschemia causes rapid structural changes and break-down of the BBB, allowing plasma exudation andimmune cell infiltration, which contribute to ischemicbrain damage [22]. Very early after the onset of brainischemia, and especially after a reperfusion period,abundant free radicals are generated in macrophages,endothelial cells, perycites, astrocytes, microglia andneurons, causing significant damage to brain capillariesand disruption of the BBB [33]. Free radicals formedboth inside and outside the vessels prompt genotoxicstress and activate PARP-1 in endothelial cells. Underconditions of chronic hypoxia, PARP-1 activationwithin endothelia triggers cell proliferation and slowlydeveloping brain damage. The molecular mechanismsof cell proliferation include the generation and releaseof ROS from NADPH oxidase and mitochondria, sus-tained increase of the cytosolic Ca2+concentrationand finally nuclear translocation of mitogen-activatedprotein kinase kinase ⁄ extracellular regulated proteinkinase with cell cycle activation [34]. Conversely,during ischemia, PARP-1 hyperactivation causes endo-thelial cell death. The latter occurs because of cellularaccumulation of the PARP-1 product poly(ADP-ribose), which causes translocation of apoptosis-induc-ing factor (AIF) from mitochondria to the nucleus andactivation of a caspase-independent programmed cell-death pathway [35–37]. Accordingly, the potentPARP-1 inhibitor, PJ34, administered to rats withtransient focal brain ischemia, preserves the integrityMMPMMP1-PRAP1-PRAP1-PRAP1-PRAP1-PRAP1-PRAPFIAFIATRPM2aC+21BGMHHMGB1yrotammalfnIsrotaidemyrotammalfnIsrotaidemXXXXMMPyrotammalfnIsrotaidemnorueNMicrogliaetycortsAetycokueLmuilehtodnEnemuLBasal laminaFig. 1. The role of PARP-1 within the ischemic neurovascular units. PARP-1 exerts its detrimental role within the ischemic neurovascularunit by promoting necrosis and AIF-dependent apoptosis in neurons, astrocytes and endothelial cells. PARP-1 also plays a key role inimmune activation and migration of microglial cells upon different noxious stimuli to the central nervous system. The expression of adhesionmolecules by endothelial cells is also promoted by PARP-1-dependent transcriptional activation, thereby promoting leukocyte recruitmentwithin the ischemic brain tissue and their detrimental effects on ischemic injury. Hence, the pharmacological inhibition of the enzyme exertsischemic neuroprotection by targeting several pleiotypic events of pathogenetic relevance to post-ischemic brain damage. X, adhesion mole-cules. ADP-ribose monomers are depicted as black circles binding to the transient receptor potential melastatin-2 receptor.F. Moroni and A. Chiarugi PARP-1 and the ischemic neurovascular unitFEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBS 39of endothelial tight junctions and decreases the expres-sion of the adhesion molecule intercellular adhesionmolecule-1, thus limiting leukocyte infiltration and thesubsequent inflammatory damage to the ischemic brain[35,38]. It has also been proposed that post-ischemicPARP-1 activation contributes to increased expressionof matrix metalloproteinases (MMPs), a group of zinc-containing proteases with key roles in matrix degrada-tion and disruption of capillary permeability duringstoke [39]. Indeed, pharmacological PARP-1 inhibitionreduces MMP-9 expression levels in plasma and brain[40], prevents brain matrix degradation, reducesdelayed increase of BBB permeability and edema for-mation, preserves endothelial tight junction proteinsand decreases delayed infiltration of leukocytes intothe brain of rats with middle cerebral artery occlusion[41]. The key role of PARP-1 hyperactivation in endo-thelial dysfunction in experimental models of diabetesunderscores the pathogenetic relevance of the enzymeto disorders of this key component of the neurovascu-lar unit [42]. Accordingly, gene array studies havedemonstrated that upregulation of inflammatory genesis hampered in PARP-1) ⁄ )endothelial cells exposed totumor necrosis factor-alfa (TNF-a) [43]. Takentogether, these findings point to basal PARP-1 activityas central to homeostatic regulation of endothelialfunction, whereas its hyperactivation appears causalto BBB damage and immune cell infiltration duringischemia.PARP-1, glia and post-ischemicinflammatory eventsActivation of resident immune cells as well as infiltra-tion of leukocytes within the ischemic area lead toexcessive release of inflammatory mediators and ensu-ing worsening of brain damage. In keeping with this,astrocytes, microglia and blood-derived leukocytescontribute to ischemic neurodegeneration, whereasimmunosuppressant strategies able to reduce theinflammatory response decrease infarct volumes in dif-ferent stroke models [16,17]. Microglial cells are resi-dent brain macrophages displaying a ‘resting’ highlyramified phenotype. Upon ischemic challenge, beforeneuronal damage can be morphologically detected [44],microglia assume amoeboid morphology and acquirephagocytic activity, producing ROS and other inflam-matory ⁄ cytotoxic factors such as nitric oxide, prosta-noids, TNF-a, IL-1b and MMPs. Astrocytes andinfiltrating leukocytes within the ischemic brain tissuealso contribute to the synthesis and release of pro-inflammatory mediators [17]. It is now widely acceptedthat the latter are responsible for disruption of thecapillary basal lamina, opening of the BBB and infil-tration of blood-borne leukocytes. This prompts avicious circle comprising waves of release of cytotoxicinflammatory products, cell death and recruit-ment ⁄ activation of blood or bystander immune cells.Eventually, the neuroimmune response causes collapseof the structures and functions of the neurovascularunit [16,17,45].Again, PARP-1 plays a key role in this scenario.Indeed, numerous reports demonstrate that PARP-1activity promotes the neuroimmune response thanksto its ability to assist transcriptional activation andepigenetic remodeling in immune cells. In this light, ithas been speculated that ischemic neuroprotectionafforded by PARP inhibitors is at least partially med-iated by their anti-inflammatory properties [46].Indeed, PARP inhibitors decrease expression ofinflammatory markers ⁄ mediators such as CD11b,cyclooxygenase-2, inducible nitric oxide synthase,TNF-a, IL-1b, IL-6, intracellular adhesion molecule-1,interferon-gamma and E-selectin in different modelsof neurodegeneration [40,47–55]. Remarkably, thesemolecules actively contribute to ischemic neurodegen-eration. A key role for PARP-1 in microglia activa-tion and migration towards injured neurons has alsobeen reported [56]. Reduced expression of pro-inflam-matory mediators is probably a result of the fact thatinflammatory transcription factors such as nuclearfactor-kappaB, activator protein-1 and nuclear factorof activated T-cells are positively regulated byPARP-1. PARP-1 protein per se , as well as its enzy-matic activity, promote transcription factor bindingto DNA as well as supramolecular complex formationcontaining several transcription-regulating proteinsand RNA polymerase II [23,53,57]. These findingstaken together may explain why post-treatment withPARP-1 inhibitors reduces the neuroimmune responsein different stroke models [58–60].Recently, the tetracycline, minocycline, has beenproposed as a clinically relevant tool to limit post-ischemic brain damage because of its ability to inhibitmicroglia activation. Minocycline is indeed able toreduce brain infarct volumes in preclinical models[61], as well as neurological impairment in strokepatients [62]. Interestingly, it has recently beenreported that minocycline is a powerful inhibitor ofPARP-1 [63]. Whether PARP-1 inhibition underpinsthe drug’s neuroprotective effects in stroke patients iscurrently unknown. Yet, given that minocycline hasbeen largely used without significant side effects, theseobservations indicate that acute inhibition of PARP-1in vivo might be a rather safe procedure and could beproposed to preserve the integrity of the ischemicPARP-1 and the ischemic neurovascular unit F. Moroni and A. Chiarugi40 FEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBSneurovascular unit and limit post-ischemic braindamage in humans.PARP-1 and post-ischemic death inneuronsExcitotoxicity and PARP-1 activation have been caus-ally linked since 1994 when it was reported that gluta-mate increases poly(ADP-ribose) synthesis and causesa type of cell death that is prevented by both NMDAantagonists and PARP-1 inhibitors [25,26]. The pro-posed molecular events underlying these observationsinclude: overactivation of NMDA glutamate receptorswith consequent intracellular Ca2+influx; and subse-quent ROS production mainly caused by neuronalnitric oxide synthase activity, which, in turn, triggersDNA damage-dependent hyperactivation of PARP-1,depletion of intracellular NAD and ATP stores, andneuronal death [26]. PARP-1 activation may also occurin neurons without NMDA receptor activation, asincreases of intracellular [Ca2+] triggered by K+-induced depolarization or inositol 3-phosphate-recep-tor activation are sufficient to trigger poly(ADP-ribose)formation [28,64]. In keeping with this toxic cascade ofevents, neurons obtained from PARP-1-deficient miceare resistant to NMDA toxicity and to oxygen andglucose deprivation [65]. It was also shown thatNMDA-induced overload of cytosolic Ca2+not onlyactivates neuronal nitric oxide synthase in the cytosol,but is also responsible for mitochondrial ROS produc-tion [66], which contributes to DNA damage and fur-ther activation of PARP-1 [67,68]. Substantial DNAdamage, evaluated by means of the comet assay, ispresent in cells isolated from the rat ischemic cortex orcaudate. NMDA receptor antagonists reduce theextent of the damage and provide ischemic neuropro-tection, while PARP inhibitors decrease infarct vol-umes without affecting the severity of DNA damage[69]. These observations suggest that NMDA receptorchannel openings, ROS formation, DNA damage andPARP activation are sequential crucial steps in theprocess leading to neuronal death. They also indicatethat stroke protection can be achieved without reduc-ing DNA damage. Energy failure following PARP-1activation is not only caused by NAD resynthesis butalso by glycolysis block because of NAD depletion,which results in reduced synthesis of both glycolysis-derived ATP and mitochondrial energetic substrates[70]. Accordingly, tricarboxylic acid cycle substrates orextracellular NAD supplementation protect neuronsfrom excessive PARP-1 activation [71], whereasPARP-1 inhibitors prevent ischemia-induced NAD+depletion and reduce ischemic brain injury [72]. Inapparent contrast to the hypothesis that PARP-1worsens ischemic neurodegeneration by reducing ATPlevels within the injured tissue, however, ischemia-induced energy derangement is similar in the affectedbrain areas of PARP-1+ ⁄ +and PARP-1) ⁄ )mice,despite the latter showing significant reduction ofischemic volumes [73].Controversy still exists on the molecular mecha-nisms involved in PARP-1-dependent neuronal deathduring ischemia. In this regard it has been veryrecently reported that exposure of cultured neuronsto poly (ADP-ribose) is sufficient to trigger nucleartranslocation of mitochondrial AIF and cell demise[74]. The poly(ADP-ribose)-degrading enzyme, poly(ADP-ribose) glycohydrolase (PARG), should be, inprinciple, a neuroprotective agent [75]. Consistently,PARG-110 kDa) ⁄ )or PARG+ ⁄ )mice show increasedsensitivity to brain ischemia [36,76]. Also, PARP-1activity seems to be essential for AIF release withinneurons of the infarct area, and AIF-deficient (Harle-quin) mice are less sensitive to post-ischemic braindamage [77]. Data therefore point to PARP-1 activ-ity-dependent AIF release from mitochondria as akey molecular event underlying ischemic neuronaldeath. Interestingly, the ADP-ribose monomers origi-nating from the polymer degradation through PARGmight also contribute to neuronal demise by activat-ing transient receptor potential melastatin-2 receptorsand massive Ca2+influx [78,79]. Finally, the findingthat, when released in the extracellular space, high-mobility-group protein box 1 (HMGB1) promotes theneuroinflammatory response and worsens brain ische-mia [80–82], along with evidence that PARP-1 pro-motes HMGB1 release [83] (but also see [82]),indicate that HMGB1 may mediate, in part, the toxiceffect of PARP-1 hyperactivation within the ischemicbrain tissue. Overall, a wealth of evidence points tothe synthesis of poly (ADP-ribose) within ischemicneurons as a crucial event contributing to derange-ment of the neurovascular unit.ConclusionTo reduce brain damage after stroke it is not sufficientto protect neurons from excitotoxic insults, but it ismandatory to rescue all cellular and structural compo-nents of the neurovascular unit. As outlined above,PARP-1 activation during brain ischemia plays a detri-mental role in all cell types of the neurovascular unit.Inhibitors of PARP-1 might therefore represent a classof ‘pleiotypic drugs’, which are considered the mostpromising tools for pharmacological treatment ofstroke. Also, the different temporal kinetics of PARP-1F. Moroni and A. Chiarugi PARP-1 and the ischemic neurovascular unitFEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBS 41activation within the components of the neurovascularunit would warrant a significant ‘window of opportu-nity’ to be harnessed for the treatment of strokepatients. Remarkably, the clinical relevance of PARP-1inhibitors in stroke treatment is emphasized by the factthat these drugs are well tolerated by patients enrolledin clinical trials for treatment of tumor malignanciesor coronary bypass, and that, theoretically, anti-stroketreatment with PARP-1 inhibitors would require anacute, 4–6-day treatment. This, of course, wouldreduce the risk of side effects. The latter might be fur-ther reduced by the forthcoming development ofPARP isoform-specific inhibitors [84]. 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Chiarugi PARP-1 and the ischemic neurovascular unitFEBS Journal 276 (2009) 36–45 ª 2008 The Authors Journal compilation ª 2008 FEBS 45 . MINIREVIEW Post -ischemic brain damage: targeting PARP-1 within the ischemic neurovascular units as a realistic avenue to stroke treatment Flavio Moroni and Alberto. pro-inflam-matory mediators is probably a result of the fact thatinflammatory transcription factors such as nuclearfactor-kappaB, activator protein-1 and
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