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MINIREVIEWPost-ischemic brain damage: the endocannabinoid systemin the mechanisms of neuronal deathDomenico E. Pellegrini-Giampietro1, Guido Mannaioni1and Giacinto Bagetta21 Department of Preclinical and Clinical Pharmacology, University of Florence, Italy2 Department of Pharmacobiology and University Center for Adaptive Disorders and Headache (UCADH), University of Calabria, Arcavacatadi Rende (CS), ItalyA wealth of information has accumulated to date con-cerning the basic mechanisms underlying post-ischemicneuronal death in the mammalian brain. In the courseof cerebral ischemia (i.e. stroke, trauma, cardiacarrest), abnormal levels of the excitatory amino acidglutamate build up in the brain, causing ‘axon-sparing’excitotoxic neuronal death. The recognized trigger forsuch a devastating event is the excessive stimulation ofglutamate receptors, particularly of the ionotropic [i.e.N-methyl-d-aspartate (NMDA)] subtype, which leadsto the accumulation of toxic amounts of intracellularfree calcium and of nitrogen and oxygen radical spe-cies, and to oxidative stress, committing the neuron todeath via activation of different downstream deathpathways selected in relation to the strength of thedetrimental stimulus [1]. This mechanism representsKeywordsananadamide; 2-arachidonoylglycerol;cannabinoids; CB receptors; cerebralischemia; endocannabinoids;neuroprotection; neurotoxicity;oxygen-glucose deprivation; strokeCorrespondenceD. E. Pellegrini-Giampietro, Department ofPharmacology, University of Florence, VialePieraccini 6, 50139 Firenze, ItalyFax: +30 055 4271 280Tel: +39 055 4271 205E-mail: domenico.pellegrini@unifi.it(Received 27 June 2008, revised 30September 2008, accepted 24 October2008)doi:10.1111/j.1742-4658.2008.06765.xAn emerging body of evidence supports a key role for the endocannabinoidsystem in numerous physiological and pathological mechanisms of the cen-tral nervous system. In the recent past, many experimental studies haveexamined the putative protective or toxic effects of drugs interacting withcannabinoid receptors or have measured the brain levels of endocannabi-noids in in vitro and in vivo models of cerebral ischemia. The results ofthese studies have been rather conflicting in supporting either a beneficialor a detrimental role for the endocannabinoid system in post-ischemic neu-ronal death, in that cannabinoid receptor agonists and antagonists haveboth been demonstrated to produce either protective or toxic responses inischemia, depending on a number of factors. Among these, the dose of theadministered drug and the specific endocannabinoid that accumulates ineach particular model appear to be of particular importance. Other mecha-nisms that have been put forward to explain these discrepant results arethe effects of cannabinoid receptor activation on the modulation of excit-atory and inhibitory transmission, the vasodilatory and hypothermic effectsof cannabinoids, and their activation of cytoprotective signaling pathways.Alternative mechanisms that appear to be independent from cannabinoidreceptor activation have also been suggested. Endocannabinoids probablyparticipate in the mechanisms that are triggered by the initial ischemicstimulus and lead to delayed neuronal death. However, further informationis needed before pharmacological modulation of the endocannabinoid sys-tem may prove useful for therapeutic intervention in stroke and relatedischemic syndromes.Abbreviations2-AG, 2-arachidonoylglycerol; AEA, anandamide; CB, cannabinoid; CNS, central nervous system; DAG, diacylglycerol; FAAH, fatty acidamide hydrolase; GABA, 4-aminobutyrate; MCAO, middle cerebral artery occlusion; NMDA, N-methyl-D-aspartate; NO, nitric oxide; OGD,oxygen-glucose deprivation; TRPV1, transient receptor potential vanilloid 1; D9-THC, D9-tetrahydrocannabinol.2 FEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBSthe rationale around which an intense area of pharma-cological research has developed during the last30 years, but which has failed to translate into clini-cally effective medicines [2]. Indeed, a large number ofclinical trials with neuroprotective drugs have yieldeddisappointing results, from the use of NMDA receptorantagonists to the most recent stroke-acute ischemicNXY treatment II (SAINT II) clinical trial, in which apromising free radical spin-trap was tested withoutsuccess [3].A probable explanation for the failure of these trialsmight be the dual role often played by mediators, suchas free radical species, that at physiological concentra-tions may be beneficial but which at high concentra-tions are detrimental for neuronal constituents. In fact,the large amounts of nitric oxide (NO) generated bypathological expression of NO synthase isoforms arecertainly neurotoxic, whereas homeostatic levels of NOproduced by the endothelial isoform of this enzymeare beneficial by, among other mechanisms, sustainingblood flow in the periphery of the ischemic brain. Onthe other hand, under normal circumstances, stimula-tion of NMDA receptors is fundamental for physiolog-ical synaptic communication and strengthening [4] and,hence, long-term blockade by competitive or noncom-petitive NMDA antagonists, as is necessary for stroketreatment, may be irrational [5]. The same reasoningcan be applied to the many other classes of anti-excito-toxic drugs tested thus far in clinical trials and cer-tainly may provide the basis for other failures in thefuture [6]. Therefore, a better design of protectivedrugs and ⁄ or protocols for stroke treatment is needed,together with the discovery of new molecular targetsfor the development of innovative and effective thera-peutic agents.During the last decade a great deal of interest hasbeen devoted to dissecting the role of the endocannabi-noid system in physiology as well as in pathologicalprocesses. The system incorporates the endocannabi-noids, their synthetic and degradative enzymes, theendocannabinoid transporters and the cannabinoid(CB) receptors, which include CB1 and CB2 receptorsas well as non-CB1 ⁄ CB2 receptors [e.g. transientreceptor potential vanilloid 1 (TRPV1) channels andpossibly others] [7–9]. The molecular cloning of twoseven-transmembrane-domain, G-protein (Gi ⁄ o)-cou-pled receptors termed CB1 [10] and CB2 [11], in con-junction with the availability of selective drugs, haveaided the comprehension of the neurobiology of thissystem. CB1 receptors, which mediate the psychotropiceffects of D9-tetrahydrocannabinol (D9-THC) andother CBs, are highly expressed in the central nervoussystem (CNS) [12] whereas CB2 receptors are almostexclusively expressed in the immune system [13,14].The best characterized endogenous ligands for CB1receptors are N-arachidonoylethanolamide (AEA,anandamide) [15] and 2-arachidonoylglycerol (2-AG)[16–18], which are biosynthesized from membrane-derived lipid precursors by, respectively, the enzymesN-acylphosphatidylethanolamine-hydrolyzing phospho-lipase D and diacylglycerol (DAG) lipase [8]. Becauseof their lipid solubility, AEA and 2-AG cannot bestored in vesicles and therefore they are synthesized ondemand and travel, in a retrograde direction, acrossthe postsynaptic membrane to the presynaptic mem-brane, where they activate presynaptic CB1 receptorsresulting in the inhibition of transmitter release[19],probably via modulation of Ca2+or K+channels[20,21]. Endocannabinoid uptake by central neuronshas been shown to be rapid, saturable, selective andtemperature dependent, implying the presence of amembrane transporter for their facilitated diffusion[22], although a specific transporter protein has yet tobe cloned. Once taken up into cells, AEA is degradedby fatty acid amide hydrolase (FAAH) [23] and 2-AGis degraded by monoacylglycerol lipase [24], althoughthe latter can also be metabolized by FAAH and otherrecently identified lipases such as the ab-hydrolases 6and 12 [8]. The endocannabinoid system in general,and CB1 receptor-mediated presynaptic inhibition inconjunction with endocannabinoid transport andenzyme metabolism in particular, have been identifiedas useful targets for neuroprotective drugs and havebeen extensively studied in experimental models ofcerebral ischemia.Endocannabinoids and CB receptorsin experimental models of cerebralischemiaIn the past 10 years, numerous studies have addressedthe role of the endocannabinoid system in stroke andin the mechanisms of post-ischemic neuronal death(Table 1). To this end, models of focal and globalischemia in vivo, with or without reperfusion, as well asmodels of oxygen glucose deprivation (OGD) in neuro-nal culture preparations in vitro, have been utilized (a)to investigate the putative protective or toxic effects ofdrugs that interact with CB receptors or that inhibitendocannabinoid catabolism or uptake, (b) to measurethe brain levels of the endocannabinoids AEA and2-AG and (c) to explore the changes in gene expressionof CB1 and CB2 receptors. Earlier reports had shownthat D9-THC may be toxic when administered chroni-cally to animals [25] but can also exert neuroprotectiveand antioxidant effects against excitotoxicity in corticalD. E. Pellegrini-Giampietro et al. The endocannabinoid system in cerebral ischemiaFEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBS 3neurons in vitro [26]. Experimental research in the fieldof ischemia was mainly prompted by observations indi-cating that CBs could attenuate glutamate-inducedinjury by inhibiting glutamate release via presynapticCB1 receptors coupled to G-proteins and N-typevoltage-gated calcium channels [20,27].An endogenous neuroprotective responseThe first CB to be tested in models of cerebral ische-mia was the synthetic cannabimimetic compound WIN55212-2 [28]. In this report, the CB receptor agonistwas neuroprotective in rats subjected to either four-vessel occlusion for 15 min (a model of transientglobal ischemia) or to permanent middle cerebralartery occlusion (MCAO). The drug was administeredintraperitoneally prior to the ischemic insult in bothmodels, but it was effective in the focal ischemicparadigm also when given up to 30 min after MCAO.The protective effect of WIN 55212-2 was observed atdoses of 0.1–1 mgÆkg)1, but not at a dose of 3 mgÆkg)1,and the protective effect appeared to be mediated byCB1 because it was prevented by co-administration ofthe antagonist rimonabant (or SR141716A). In thesame study, WIN 55212-2 was also tested in corticalneurons exposed to OGD for 8 h, but neuroprotectionin vitro lacked stereoselectivity, was insensitive to CB1and CB2 receptor antagonists, and was not mimickedby D 9-THC, suggesting a non-CB receptor-mediatedmechanism of action. When the same group observedan increase in CB1 receptor expression in the penum-bral boundary zone, starting at 2 h and persisting forat least 72 h after a transient MCAO episode [29], thisfinding was interpreted as an endogenous neuroprotec-tive response. Subsequent reports appeared to corrobo-rate this view, by demonstrating that natural andsynthetic CBs could attenuate neuronal injury in mod-els of global [30,31] and focal [32–34] ischemia in vivo,although, at least in models of permanent MCAO,CB1-induced hypothermia appeared to contribute toTable 1. The endocannabinoid system in experimental models of cerebral ischemia. 2VO, two-vessel occlusion; 4VO, four-vessel occlusion;AEA, anandamide; 2-AG, 2-arachidonoylglycerol; CB, cannabinoid; CB-R, CB receptor; eCB, endocannabinoid; n.t., not tested; pMCAO,permanent middle cerebral artery occlusion; tMCAO, transient middle cerebral artery occlusion. ›, increased; fl, decreased; =, no change.Model CB-R activation eCB levels ⁄ CB-R expression ReferenceTransient global ischemiaRat 4VO (15 min) Protection [28]Rat hypotension + 2VO (12 min) Protection [30]Gerbil 2VO (10 min) Protection [31]Rat 4VO (7 min) Protection [37]Gerbil 2VO (10 min) Toxicity [48]Gerbil 2VO (10 min) Protection [38]Focal ischemiaRat pMCAO (24 h) Protection [28]Rat tMCAO NT ›CB1 (cortex) [29]Mouse tMCAO (20 min) Protection CB1-KO mice [35]Rat tMCAO (1 h) Protection [32]Rat pMCAO (72 h) Protection [33]Mouse tMCAO (20 min) NT ›AEA = 2-AG [105]Mouse tMCAO (4 h) Protection [34]Rat tMCAO (2 h) Toxicity ›AEA = 2-AG [44]Rat pMCAO (5 h) Toxicity ›AEA [46]Rat pMCAO (5 h) Toxicity =[3H]CP 55 940 binding [47]Rat tMCAO (2 h) Toxicity ›AEA (striatum) late fl AEA (cortex) [45]Mouse pMCAO (24 h) Protection ›2-AG = AEA [39]Rat pMCAO (72 h) NT ›CB2 (microglia) [40]Mouse tMCAO (1 h) Protection (CB2) [41]Mouse tMCAO (1 h) Toxicity ›CB1 & CB2 [53]Oxygen-glucose deprivation in vitroRat cortical neurons (8 h) Protection [28]Rat cortical neurons (8 h) Protection [36]Mouse midbrain slices (7 min) Protection ›2-AG = AEA [37]Rat cortiscostriatal slices (30 min) Protection ›CB1 = CB2 [42]Hippocampal slices (15 min) Toxicity [52]The endocannabinoid system in cerebral ischemia D. E. Pellegrini-Giampietro et al.4 FEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBSneuroprotection [32,33]. Consistent with these findings,CB1 receptor-deficient mice exhibited increased suscep-tibility to NMDA neurotoxicity, as well as increasedmortality and a larger infarct size following permanentfocal ischemia [35].Experimental studies in vitro confirmed that theendocannabinoids AEA and 2-AG may attenuateOGD injury in cortical cells, although via CB1-inde-pendent and CB2-independent mechanisms [36], andthat the CB receptor agonist WIN 55212-2, at low(3–30 nm) concentrations, but not at higher concen-trations (100–1000 nm), prevented excessive mem-brane depolarization and delayed the onset ofdepolarization block in ventral tegmental area dopa-minergic neurons exposed to OGD [37]. In the latterstudy, the CB1 antagonist AM281 and the DAG-lipase inhibitor, O-3640, exacerbated the detrimentaleffects of OGD in vitro by releasing glutamate inexcess, indicating that the increase in 2-AG levelsthat was observed by these authors following OGDmay protect dopaminergic neurons through a mecha-nism similar to depolarization-induced suppression ofexcitation (see below). A similar noxious effect wasdemonstrated with another CB1 antagonist, rimona-bant (1 mgÆkg)1intravenously), on the outcome oftransient forebrain ischemia in rats [37]. Neuropro-tective effects were also obtained in vivo with theendocannabinoid transporter inhibitor AM404 [38]and with the FAAH inhibitor URB597 [39], thussuggesting the contribution of anandamide to thebeneficial effects of CBs observed in these models.A role for CB2 receptors?Although CB2 receptors are not expressed in neuronsand were generally believed to be absent from the brain,it has been shown that CB2-positive macrophages,deriving from resident microglia and ⁄ or invadingmonocytes, appear in rat brain 3 days after hypoxia ⁄ischemia or permanent MCAO [40]. The CB2 agonistsO-3853 and O-1966 have been shown to reduce theinfarct size and to improve the neurological score inmice 24 h after a transient episode of MCAO [41],indicating that activation of CB2 may be important inreducing inflammatory responses that may lead to sec-ondary injury following cerebral ischemia. In anotherstudy, both CB1 and CB2 receptor agonists were ableto prevent the cellular damage, the efflux of lactatedehydrogenase, the release of glutamate and tumornecrosis factor-a, and the expression of inducible NOsynthase caused by OGD in cortico-striatal slices, butonly CB1 receptors (not CB2 receptors) were signifi-cantly increased following the ischemia-like insult [42].The ‘dark side’ of CBsAn independent line of research supports a contrast-ing, neurotoxic role for CB receptor activation inischemia, a role that was referred to as the ‘dark side’of endocannabinoids in a report describing the toxiceffects of intracerebroventricular administration ofanandamide [43]. In these studies, neuroprotectiveeffects on post-ischemic neuronal death were providedby CB1 receptor antagonists, and in particular byrimonabant. Muthian et al. [44] showed that pretreat-ment with 3 mgÆkg)1rimonabant, but not with 0.3 or1mgÆkg)1rimonabant, produced a 50% reduction ininfarct volume and a 40% improvement in neurologi-cal function in rats subjected to MCAO for 2 h. Theprotective effect was not observed with the CB agonistWIN 55212-2 (up to 1 mgÆkg)1) and was associatedwith an increase in the brain content of anandamide.A similar neuroprotection with 3 mgÆkg)1rimonabantbut not with WIN 55212-2 was reported in the samemodel by Amantea et al. [45], who were able to corre-late the persistent post-ischemic increase in the levelsof striatal anandamide with an increased activity ofN-acylposphatidylethanolamine-hydrolyzing phospholi-pase D and reduced activity and expression of FAAH.Both the accumulation of anandamide (and of otherN-acylethanolamines) and the protective effects ofrimonabant (at 1 mgÆkg)1) were also observed in a ratpermanent MCAO model [46]: the CB1 antagonist,however, was unable to counteract the elevation inanandamide levels or the ischemic release of glutamate.A subsequent study by the same group showed thatrimonabant was able to prevent the ischemic down-regulation of NMDA receptors in the penumbra [47],confirming that the protective effects of this CB1receptor antagonist are unlikely to be related to ananti-excitotoxic mechanism. A contribution of TRPV1channels to rimonabant-induced neuroprotection hasbeen proposed by the observation that the TRPV1antagonist capsazepine completely prevents the attenu-ation of CA1 pyramidal cell loss induced by rimona-bant in gerbils subjected to transient forebrainischemia [48]. In this study, the protective effects ofrimonabant exhibited a bell-shaped curve, as previ-ously observed for WIN 55212-2 [28,37], and wereobserved at relatively low doses (0.25–0.5 mgÆkg)1)compared with the results of other studies. To confirmthe crucial role of TRPV1 channels in neurodegenera-tive disorders [49], it is worth noting that capsazepinehas also been reported to prevent the neuroprotectiveeffects of the agonist capsaicin in models of globalischemia [50] and ouabain-induced toxicity in vivo[51]. The only other CB1 antagonist that has shownD. E. Pellegrini-Giampietro et al. The endocannabinoid system in cerebral ischemiaFEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBS 5beneficial effects in ischemic models so far is the com-pound AM251, which was able, at 1 lm, to improvemarkedly the post-OGD recovery of synaptic transmis-sion in acute hippocampal slices [52]. In a very recentstudy, the beneficial effects of rimonabant in a modelof focal ischemia were mimicked and potentiated bythe CB2 agonist O-1966 [53], suggesting that themodulation of the balance between CB1 and CB2receptor activities may represent an intriguing novelpossibility for ischemic therapeutic approaches.The endocannabinoid system incerebral ischemia – a neuroprotectiveor a neurotoxic mechanism?The almost ubiquitous presence of the endocannabi-noid machinery in every cell of the CNS, together withthe high level of CB1 receptor expression in criticalbrain regions (cerebellum, hippocampus, neocortexand basal ganglia), highlights the endocannabinoid sys-tem as an important modulator and possible pharma-cological target for many physiological mechanisms(i.e. learning, memory, appetite control, the rewardsystem) and pathological conditions, such as pain,anxiety, mood disorders, motor disturbances and neuro-degenerative diseases, including cerebral ischemia[8,54,55]. As discussed, the scientific literature on neu-rodegenerative disorders, and specifically on ischemiaresearch (Table 1), has not always been consistent insustaining either a beneficial or a detrimental role forthe endocannabinoid system in the CNS [9,55–57]. CBreceptor agonists and antagonists have both been dem-onstrated to produce either protective or toxicresponses in ischemia, depending on a number of fac-tors. Among these, two of the most important appearto be (a) the dose of the administered CB drug and (b)the specific endocannabinoid that accumulates in eachparticular model. Indeed, in some studies, the CB ago-nist WIN 55212-2 appears to exert protective effectsin vivo at 0.1–1 mgÆkg)1intraperitoneally but not athigher doses [28,37], whereas the antagonist rimona-bant displays neuroprotection at 0.25–0.5 mgÆkg)1buta certain degree of toxicity at 3 mgÆkg)1[48]. Anothervery striking feature emerging from the experimentalstudies in models of cerebral ischemia is the fact thatwhen CB receptors mediate neurotoxicity (i.e. CBreceptor agonists are toxic and ⁄ or antagonists are pro-tective) the endocannabinoid that is increased follow-ing ischemia is always AEA, and not 2-AG [44–46],whereas the opposite appears to occur when CB recep-tors mediate neuroprotection [37,39] (Table 1). Thispeculiar phenomenon may be a result of the fact thatAEA and other N-acethylethanolamines, but not2-AG, are known to activate and desensitize TRPV1receptors (see below).Numerous hypotheses have been put forward in thepast few years to reconcile these discrepant and con-troversial findings. In the following sections, we willreview some of the most important mechanisms thathave been proposed to date in an attempt to explainthe reasons whereby activation of CB receptors maylead to either neuroprotection or neurotoxicity inmodels of neurodegeneration and ischemia.Modulation of excitatory and inhibitoryneurotransmissionIn neurons, CB1 receptors are mainly localized onaxon presynaptic terminals and thereby they play animportant role in the regulation of neurotransmitterrelease [19,58]. More specifically, CB1 receptor activa-tion by endocannabinoids has been shown to inhibiteither glutamatergic [59–62] or GABAergic [63,64] syn-aptic transmission, depending on the brain region,through a presynaptic mechanism. The current ‘molec-ular logic’ on the endocannabinoid system signaling [7]predicts that AEA and 2-AG are synthesized ondemand in the membrane of postsynaptic neurons,then immediately released into the synaptic cleft wherethey retrogradely diffuse to activate CB1 receptors onpresynaptic terminals, which eventually leads to inhibi-tion of N-type calcium currents and suppression of cellexcitability and neurotransmitter release [65–67](Fig. 1). Indeed, this view is corroborated, at least for2-AG, by the findings that DAG lipases are expressedin the dendritic postsynaptic compartment [68],whereas monoacylglycerol lipase is primarily a presyn-aptic enzyme [69]. Presynaptic CB1 receptor activationin different brain areas has been associated with themodulation of important synaptic plasticity pheno-mena, such as depolarization-induced suppression ofinhibition [66,70], depolarization-induced suppressionof excitation [67,71], persistent suppression of evokedinhibitory postsynaptic currents [72] and inhibitorylong-term depression [73]. All of these CB1-mediatedmechanisms, often driven by a functional interactionwith metabotropic glutamate receptors, tightly regulatethe synaptic concentrations of either glutamate orGABA, depending on the brain area. Hence, the dif-ferential inhibition of glutamate or GABA in variousexperimental models of cerebral ischemia may be oneof the principal reasons whereby activation of CBreceptors may lead to either neuroprotection or neuro-toxicity (Fig. 1). Interestingly, a similar mechanism hasbeen observed in different models of hippocampalepileptic seizures: when endocannabinoids target gluta-The endocannabinoid system in cerebral ischemia D. E. Pellegrini-Giampietro et al.6 FEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBSmatergic neurons they provide neuroprotection [74,75],whereas when they suppress GABAergic transmissionthey enhance hyperexcitability [76,77].Recently, a novel endocannabinoid–glutamate sig-naling pathway that may be of relevance in mediatingthe physiological and pathological effects of CBs inthe hippocampus has been described [78]. This mecha-nism involves a neuron–astrocyte communication, inwhich endocannabinoids released by neurons activateCB1 receptors located in astrocytes, leading to phos-pholipase C-dependent Ca2+mobilization from astro-cytic internal stores, astrocytic release of glutamateand eventually activation of NMDA receptors in pyra-midal cells.Vasodilation and hypothermiaActivation of CB1 receptors in cerebral blood vesselsresults in decreased vascular resistance and increasedblood flow [79–81]. CB receptor-mediated cerebralvasodilation may have beneficial effects in ischemicbrain but may also lead to a loss of cerebrovascularautoregulation and hence to an unfavorable outcome,at least in MCAO models [82,83]. AEA and 2-AG mayalso produce vasodilation through a TRPV1-mediatedmechanism [84], possibly involving the production ofNO from endothelial cells [85–87]. It should be noted,however, that 2-AG was unable to reproduce the vaso-dilator response of AEA via TRPV1 receptors inanother study [88].The reduction in brain temperature by bothD9-THC and synthetic CBs has been proposed as animportant possible mechanism underlying the neuro-protective effects of endocannabinoids. Warming theanimals to the body temperature of controls preventedthe neuroprotective effects of CB1 agonists in somestudies using models of focal [33,34] and global [38]cerebral ischemia. However, it should be taken intoaccount that D9-THC was shown to be neuroprotec-tive also at doses that were not hypothermic [38] or inanimals where temperature was under rigorous control[30]. CB1 receptors located in the pre-optic anteriorhypothalamic nucleus have been suggested to be theprimary mediators of CB-induced hypothermia [89].Activation of cytoprotective/anti-apoptoticsignaling pathwaysBiochemical pathways that trigger apoptotic cell deathor cytoprotective cellular mechanisms can be differen-tially affected by CB receptor activation. Initially,D9-THC was demonstrated to induce apoptosis incultured hippocampal neurons and slices [90]. Morerecently, D9-THC and other CBs have revealed thatCB1 receptors are coupled, in a rimonabant-dependentmanner, to the anti-apoptotic phosphatidylinositol3-kinase ⁄ Akt signaling pathway [91,92]. Activation ofthis pathway appears to mediate the neuroprotectiveeffects of CBs in oligodendrocytes [93] and neurons[94]. Furthermore, genetic suppression or pharmaco-logical antagonism of CB1 receptors blocks the pro-duction of brain-derived neurotrophic factor followingtoxic administration of kainic acid [74,95], suggestingthat brain-derived neurotrophic factor may be anotherimportant mediator of the neuroprotective effects ofCBs.CB receptor-independent mechanismsA number of potentially neuroprotective as well asneurotoxic effects of CBs do not appear to be medi-ated by direct activation of CB receptors. For example,some CBs, including D9-THC, possess antioxidantproperties and protect various cell types against oxida-tive stress [26,96], an effect that has been demonstratedGlutamatergicterminal G A B A GlutamateCB 1 GABAergic terminal Soma Spine Neurotoxicity NeuroprotectionDAG-L NAPE-PLD 2-AG AEA CB 1 Fig. 1. Schematic model providing a hypothetic mechanism thatinvolves the modulation of GABAegic and glutamate release for thedual toxic ⁄ protective role played by the endocannabinoid system inpost-ischemic neuronal death. At the postsynaptic membrane level,the endocannabinoids anandamide (AEA) and 2-arachidonoylglycerol(2-AG) are biosynthesized, respectively, by the enzymes N-acyl-phosphatidylethanolamine-hydrolyzing phospholipase D (NAPE-PLD)and diacylglycerol lipase (DAG-L). Immediately after the synthesisAEA and 2-AG are released into the synaptic cleft, from which theydiffuse retrogradely to activate presynaptic cannabinoid 1 (CB1)receptors. Depending on the brain region or the experimentalmodel, CB1 receptors can be localized on the presynaptic terminalsof either GABAergic or glutamatergic neurons, promoting, alterna-tively, the suppression of the release of GABA, which is a poten-tially neurotoxic mechanism, or of glutamate, which instead maylead to neuroprotection.D. E. Pellegrini-Giampietro et al. The endocannabinoid system in cerebral ischemiaFEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBS 7to depend on the phenolic structure of the compoundsand not on their interaction with CB1 receptors [97].Moreover, AEA and other N-acylethanolamines thatare known to accumulate in rodent models of perma-nent MCAO [39,46] may elicit biological cytotoxiceffects through targets other than CB receptors [43].Among them, in mouse epidermal JB6 cells, AEA andN-acylethanolamines stimulate CB-independent extra-cellular regulated kinase phosphorylation and, athigher concentrations, have profound cytotoxic effectsowing to a collapse of mitochondrial energy metabo-lism, which compromises mitochondrial function [98].One of the most important CB receptor-independentmechanisms underlying the neurotoxic effects of CBsmight involve the activation of vanilloid receptors suchas TRPV1. AEA has been demonstrated to activateTRPV1 channels both in vitro and in vivo and to upre-gulate genes involved in pro-inflammatory ⁄microglial-related responses [43,99,100]. In addition, AEA caninduce an acute release of NO through endothelialTRPV1 activation [87], which may be responsible forCB-induced vasorelaxation and hence has beneficial, butalso detrimental, effects (see above) in models of ische-mia. It has been suggested that rimonabant, by blockingCB1 receptors, leads to neuroprotection against excito-toxicity and ischemia because the increased concentra-tions of N-acylethanolamines, including AEA, activateand desensitize TRPV1 receptors [48,51].Recently, the G-protein-coupled receptor GPR55has been proposed as a new CB receptor with signalingpathways distinct from those of classical CB1 ⁄ CB2receptors [101]. Activation of GPR55 increasesintracellular Ca2+concentrations and inhibits M-typeK+-channel currents, thereby enhancing neuronalexcitability [101] and potentially toxic events ifexpressed in neurons.Concluding remarksThe great deal of knowledge accumulated in the pastthree decades on the mechanisms underlying damageinflicted to the brain tissue by cerebral ischemia hasfailed to translate into effective medicines. Mostrecently, a renewed interest towards molecular targetsfor the development of novel stroke therapies has beenstimulated by the detailed description of the endocann-abinoid system in the mammalian brain. This has beenaccomplished thanks to the current availability ofdrugs to target not only CB1 and CB2 receptors, butalso the biosynthesis, metabolism and transport ofendocannabinoids. As discussed, conflicting resultshave accumulated with the use of drugs targeting CB1receptors in models of cerebral ischemia, which maydepend on the experimental model, the dose of drugadministered and the specific endocannabinoid thataccumulates. Recent reviews have attempted to explainthese discrepancies by proposing that endocannabi-noids may act as protective agents only in a time- andspace-specific manner, whereas they might contributeto neurodegeneration if their action loses specificity[8,102–104]. Probably, a more definitive role for CB2receptor antagonists as anti-inflammatory drugs can beanticipated, although the efficacy in the clinic settingsstill awaits a conclusive demonstration. It is conceiv-able that in the course of cerebral ischemia, as docu-mented in the recent past for other endogenoustargets, endocannabinoids participate in a complexseries of events initiated by the detrimental stimulus.However, further information is needed beforepharmacological modulation of the endocannabinoidsystem may prove useful for therapeutic intervention.AcknowledgementsThis work was supported by grants from the ItalianMinistry of University and Research (MIUR, PRIN2006 project) to DEPG and GB, by the University ofFlorence to DEPG and GM, and by the University ofCalabria to GB.References1 Bonfoco E, Krainc D, Ankarcrona M, Nicotera P &Lipton SA (1995) Apoptosis and necrosis: two distinctevents induced, respectively, by mild and intense insultswith N-methyl-d-aspartate or nitric oxid ⁄ superoxide incortical cell cultures. Proc Natl Acad Sci USA 92,7162–7166.2 Gladstone DJ, Black SE & Hakim AM (2002) Towardwisdom from failure: lessons from neuroprotectivestroke trials and new therapeutic directions. Stroke 33,2123–2136.3 Shuaib A, Lees KR, Lyden P, Grotta J, Davalos A,Davis SM, Diener H, Ashwood T, Wasiewski WW &Emeribe U (2007) NXY-059 for the treatment of acuteischemic stroke. N Engl J Med 357, 562–571.4 Bliss TVP & Collingridge GL (1993) A synaptic modelof memory: long-term potentiation in the hippocam-pus. Nature 361, 31–39.5 Olney JW, Labruyere J, Wang G, Wozniak DF, PriceMT & Sesma MA (1991) NMDA antagonist neurotoxic-ity: mechanism and prevention. Science 254, 1515–1518.6 Grotta J (2002) Neuroprotection is unlikely to be effec-tive in humans using current trial designs. Stroke 33,306–307.7 Piomelli D (2003) The molecular logic of endocannabi-noid signalling. Nat Rev Neurosci 4, 873–884.The endocannabinoid system in cerebral ischemia D. E. Pellegrini-Giampietro et al.8 FEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBS8 Di Marzo V (2008) Targeting the endocannabinoid sys-tem: to enhance or reduce? Nat Rev Drug Discov 7,438–455.9 Di Marzo V & Petrosino S (2007) Endocannabinoidsand the regulation of their levels in health and disease.Curr Opin Lipidol 18, 129–140.10 Matsuda LA, Lolait SJ, Brownstein MJ, Young AC &Bonner TI (1990) Structure of a cannabinoid receptorand functional expression of the cloned cDNA. Nature346, 561–564.11 Munro S, Thomas KL & Abu-Shaar M (1993) Molecu-lar characterization of a peripheral receptor for canna-binoids. Nature 365, 61–65.12 Herkenham M, Lynn AB, Little MD, Johnson MR,Melvin LS, Decosta BR & Rice KC (1990) Cannabi-noid receptor localization in brain. Proc Natl Acad SciUSA 87, 1932–1936.13 Skaper SD, Buriani A, Dal Toso R, Petrelli L, Roma-nello S, Facci L & Leon A (1996) The ALIAmidepalmitoylethanolamide and cannabinoids, but notanandamide, are protective in a delayed postglutamateparadigm of excitotoxic death in cerebellar granuleneurons. Proc Natl Acad Sci USA 93, 3984–3989.14 Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A,Urbani P, Mackie K, Stella N, Makriyannis A, Piomel-li D, Davison JS et al. (2005) Identification and func-tional characterization of brainstem cannabinoid CB2receptors. Science 310, 329–332.15 Devane WA, Hanus L, Breuer A, Pertwee RG, Steven-son LA, Griffin G, Gibson D, Mandelbaum A, EtingerA & Mechoulam R (1992) Isolation and structure of abrain constituent that binds to the cannabinoid recep-tor. Science 258, 1946–1949.16 Mechoulam R, Benshabat S, Hanus L, Ligumsky M,Kaminski NE, Schatz AR, Gopher A, Almog S, Mar-tin BR, Compton DR et al. (1995) Identification of anendogenous 2-monoglyceride, present in canine gut,that binds to cannabinoid receptors. Biochem Pharma-col 50, 83–90.17 Stella N, Schweitzer P & Piomelli D (1997) A secondendogenous cannabinoid that modulates long-termpotentiation. Nature 388, 773–778.18 Sugiura T, Kondo S, Sukagawa A, Nakane S, ShinodaA, Itoh K, Yamashita A & Waku K (1995) 2-Arachi-donoylglycerol: a possible endogenous cannabinoidreceptor ligand in brain. Biochem Biophys Res Commun215, 89–97.19 Schlicker E & Kathmann M (2001) Modulation oftransmitter release via presynaptic cannabinoid recep-tors. Trends Pharmacol Sci 22, 565–572.20 Mackie K & Hille B (1992) Cannabinoids inhibitN-type calcium channels in neuroblastoma-glioma cells.Proc Natl Acad Sci USA 89, 3825–3829.21 Daniel H & Crepel F (2001) Control of Ca(2+) influxby cannabinoid and metabotropic glutamate receptorsin rat cerebellar cortex requires K(+) channels. J Phys-iol 537, 793–800.22 Di Marzo V, Fontana A, Cadas H, Schinelli S, CiminoG, Schwartz JC & Piomelli D (1994) Formation andinactivation of endogenous cannabinoid anandamide incentral neurons. Nature 372, 686–691.23 McKinney MK & Cravatt BF (2005) Structure andfunction of fatty acid amide hydrolase. Annu Rev Bio-chem 74, 411–432.24 Dinh TP, Carpenter D, Leslie FM, Freund TF, KatonaI, Sensi SL, Kathuria S & Piomelli D (2002) Brainmonoglyceride lipase participating in endocannabinoidinactivation. Proc Natl Acad Sci USA 99, 10819–10824.25 Scallet AC (1991) Neurotoxicology of cannabis andTHC: a review of chronic exposure studies in animals.Pharmacol Biochem Behav 40, 671–676.26 Hampson AJ, Grimaldi M, Axelrod J & Wink D(1998) Cannabidiol and (-)Delta9-tetrahydrocannabinolare neuroprotective antioxidants. Proc Natl Acad SciUSA 95, 8268–8273.27 Shen M, Piser TM, Seybold VS & Thayer SA (1996)Cannabinoid receptor agonists inhibit glutamatergicsynaptic transmission in rat hippocampal cultures.J Neurosci 16, 4322–4334.28 Nagayama T, Sinor AD, Simon RP, Chen J, GrahamSH, Jin K & Greenberg DA (1999) Cannabinoids andneuroprotection in global and focal cerebral ischemiaand in neuronal cultures. J Neurosci 19, 2987–2995.29 Jin KL, Mao XO, Goldsmith PC & Greenberg DA(2000) CB1 cannabinoid receptor induction in experi-mental stroke. Ann Neurol 48, 257–261.30 Louw DF, Yang FW & Sutherland GR (2000) Theeffect of delta-9-tetrahydrocannabinol on forebrainischemia in rat. Brain Res 857, 183–187.31 Braida D, Pozzi M & Sala M (2000) CP 55,940 pro-tects against ischemia-induced electroencephalographicflattening and hyperlocomotion in Mongolian gerbils.Neurosci Lett 296, 69–72.32 Mauler F, Hinz V, Augstein KH, Fassbender M &Horvath E (2003) Neuroprotective and brain edema-reducing efficacy of the novel cannabinoid receptoragonist BAY 38-7271. Brain Res 989, 99–111.33 Leker RR, Gai N, Mechoulam R & Ovadia H (2003)Drug-induced hypothermia reduces ischemic damage:effects of the cannabinoid HU-210. Stroke 34, 2000–2006.34 Hayakawa K, Mishima K, Abe K, Hasebe N, Takama-tsu F, Yasuda H, Ikeda T, Inui K, Egashira N, Iwasa-ki K et al. (2004) Cannabidiol prevents infarction viathe non-CB1 cannabinoid receptor mechanism. Neuro-Report 15, 2381–2385.35 Parmentier-Batteur S, Jin K, Mao XO, Xie L & Green-berg DA (2002) Increased severity of stroke in CB1cannabinoid receptor knock-out mice. J Neurosci 22,9771–9775.D. E. Pellegrini-Giampietro et al. The endocannabinoid system in cerebral ischemiaFEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBS 936 Sinor AD, Irvin SM & Greenberg DA (2000) Endoc-annabinoids protect cerebral cortical neurons from invitro ischemia in rats. Neurosci Lett 278, 157–160.37 Melis M, Pillolla G, Bisogno T, Minassi A, PetrosinoS, Perra S, Muntoni AL, Lutz B, Gessa GL,Marsicano G et al. (2006) Protective activation of theendocannabinoid system during ischemia in dopamineneurons. Neurobiol Dis 24, 15–27.38 Zani A, Braida D, Capurro V & Sala M (2007) D9-tet-rahydrocannabinol (THC) and AM 404 protect againstcerebral ischaemia in gerbils through a mechanisminvolving cannabinoid and opioid receptors. Br J Phar-macol 152, 1301–1311.39 Degn M, Lambertsen KL, Petersen G, Meldgaard M,Artmann A, Clausen BH, Hansen SH, Finsen B, Han-sen HS & Lund TM (2007) Changes in brain levels ofN-acylethanolamines and 2-arachidonoylglycerol infocal cerebral ischemia in mice. J Neurochem 103 ,1907–1916.40 Ashton JC, Rahman RM, Nair SM, Sutherland BA,Glass M & Appleton I (2007) Cerebral hypoxia-ische-mia and middle cerebral artery occlusion induceexpression of the cannabinoid CB2 receptor in thebrain. Neurosci Lett 412, 114–117.41 Zhang M, Martin BR, Adler MW, Razdan RK, JalloJI & Tuma RF (2007) Cannabinoid CB(2) receptoractivation decreases cerebral infarction in a mousefocal ischemia ⁄ reperfusion model. J Cereb Blood FlowMetab 27, 1387–1396.42 Fernandez-Lopez D, Martinez-Orgado J, Nunez E,Romero J, Lorenzo P, Moro MA & Lizasoain I (2006)Characterization of the neuroprotective effect of thecannabinoid agonist WIN-55212 in an in vitro modelof hypoxic-ischemic brain damage in newborn rats.Pediatr Res 60, 169–173.43 Cernak I, Vink R, Natale J, Stoica B, Lea PM, Mov-sesyan V, Ahmed F, Knoblach SM, Fricke ST &Faden AI (2004) The ‘‘dark side’’ of endocannabinoids:a neurotoxic role for anandamide. J Cereb Blood FlowMetab 24, 564–578.44 Muthian S, Rademacher DJ, Roelke CT, Gross GJ &Hillard CJ (2004) Anandamide content is increasedand CB1 cannabinoid receptor blockade is protectiveduring transient, focal cerebral ischemia. Neuroscience129, 743–750.45 Amantea D, Spagnuolo P, Bari M, Fezza F, Mazzei C,Tassorelli C, Morrone LA, Corasaniti MT, Maccar-rone M & Bagetta G (2007) Modulation of the endoc-annabinoid system by focal brain ischemia in the rat isinvolved in neuroprotection afforded by 17beta-estra-diol. FEBS J 274, 4464–4775.46 Berger C, Schmid PC, Schabitz WR, Wolf M, SchwabS & Schmid HH (2004) Massive accumulation ofN-acylethanolamines after stroke. Cell signalling inacute cerebral ischemia? J Neurochem 88, 1159–1167.47 Sommer C, Schomacher M, Berger C, Kuhnert K,Muller HD, Schwab S & Schabitz WR (2006) Neuro-protective cannabinoid receptor antagonist SR141716Aprevents downregulation of excitotoxic NMDA recep-tors in the ischemic penumbra. Acta Neuropathol 112,277–286.48 Pegorini S, Zani A, Braida D, Guerini-Rocco C & SalaM (2006) Vanilloid VR1 receptor is involved in rimo-nabant-induced neuroprotection. Br J Pharmacol 147,552–559.49 Starowicz K, Cristino L & Di Marzo V (2008) TRPV1receptors in the central nervous system: potential forpreviously unforeseen therapeutic applications. CurrPharm Des 14, 42–54.50 Pegorini S, Braida D, Verzoni C, Guerini-Rocco C,Consalez GG, Croci L & Sala M (2005) Capsaicinexhibits neuroprotective effects in a model of transientglobal cerebral ischemia in Mongolian gerbils. Br JPharmacol 144, 727–735.51 Veldhuis WB, van der Stelt M, Wadman MW, vanZadelhoff G, Maccarrone M, Fezza F, Veldink GA,Vliegenthart JFG, Bar PR, Nicolay K et al. (2003)Neuroprotection by the endogenous cannabinoidanandamide and arvanil against in vivo excitotoxicityin the rat: role of vanilloid receptors and lipoxygenases.J Neurosci 23, 4127–4133.52 Youssef FF, Hormuzdi SG, Irving AJ & Frenguelli BG(2007) Cannabinoid modulation of neuronal functionafter oxygen ⁄ glucose deprivation in area CA1 of therat hippocampus. Neuropharmacology 52, 1327–1335.53 Zhang M, Martin BR, Adler MW, Razdan RK, GaneaD & Tuma RF (2008) Modulation of the balancebetween cannabinoid CB(1) and CB(2) receptor activa-tion during cerebral ischemic ⁄ reperfusion injury.Neu-roscience 152, 753–760.54 Fowler CJ, Holt S, Nilsson O, Jonsson KO, Tiger G &Jacobsson SO (2005) The endocannabinoid signalingsystem: pharmacological and therapeutic aspects. Phar-macol Biochem Behav 81, 248–262.55 Pacher P & Hasko G (2008) Endocannabinoids andcannabinoid receptors in ischaemia-reperfusion injuryand preconditioning. Br J Pharmacol 153, 252–262.56 Guzman M (2003) Neurons on cannabinoids: dead oralive? Br J Pharmacol 140, 439–440.57 van der Stelt M & Di Marzo V (2005) Cannabinoidreceptors and their role in neuroprotection. Neuro-molecular Med 7, 37–50.58 Freund TF, Katona I & Piomelli D (2003) Role ofendogenous cannabinoids in synaptic signaling. PhysiolRev 83 , 1017–1066.59 Gerdeman G & Lovinger DM (2001) CB1 cannabinoidreceptor inhibits synaptic release of glutamate in ratdorsolateral striatum. J Neurophysiol 85, 468–471.60 Galante M & Diana MA (2004) Group I metabotropicglutamate receptors inhibit GABA release atThe endocannabinoid system in cerebral ischemia D. E. Pellegrini-Giampietro et al.10 FEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBSinterneuron-Purkinje cell synapses through endocanna-binoid production. J Neurosci 24, 4865–4874.61 Nemeth B, Ledent C, Freund TF & Hajos N (2008)CB1 receptor-dependent and -independent inhibition ofexcitatory postsynaptic currents in the hippocampus byWIN 55,212-2. Neuropharmacology 54, 51–57.62 Domenici MR, Azad SC, Marsicano G, Schierloh A,Wotjak CT, Dodt HU, Zieglgansberger W, Lutz B &Rammes G (2006) Cannabinoid receptor type 1 locatedon presynaptic terminals of principal neurons in theforebrain controls glutamatergic synaptic transmission.J Neurosci 26, 5794–5799.63 Hajos N, Katona I, Naiem SS, Mackie K, Ledent C,Mody I & Freund TF (2000) Cannabinoids inhibit hip-pocampal GABAergic transmission and network oscil-lations. Eur J Neurosci 12, 3239–3249.64 Katona I, Sperlagh B, Sik A, Kafalvi A, Vizi ES, Mac-kie K & Freund TF (1999) Presynaptically located CB1cannabinoid receptors regulate GABA release fromaxon terminals of specific hippocampal interneurons.J Neurosci 19, 4544–4558.65 Ohno-Shosaku T, Maejima T & Kano M (2001)Endogenous cannabinoids mediate retrograde signalsfrom depolarized postsynaptic neurons to presynapticterminals. Neuron 29, 729–738.66 Wilson RI & Nicoll RA (2001) Endogenous cannabi-noids mediate retrograde signalling at hippocampalsynapses. Nature 410, 588–592.67 Kreitzer AC & Regehr WG (2001) Retrograde inhibi-tion of presynaptic calcium influx by endogenous cann-abinoids at excitatory synapses onto Purkinje cells.Neuron 29, 717–727.68 Bisogno T, Howell F, Williams G, Minassi A, CascioMG, Ligresti A, Matias I, Schiano-Moriello A, Paul P,Williams EJ et al. (2003) Cloning of the first sn1-DAGlipases points to the spatial and temporal regulation ofendocannabinoid signaling in the brain. J Cell Biol163, 463–468.69 Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomel-li D, Boscia F & Freund TF (2004) Segregation of twoendocannabinoid-hydrolyzing enzymes into pre- andpostsynaptic compartments in the rat hippocampus,cerebellum and amygdala. Eur J Neurosci 20, 441–458.70 Alger BE, Pitler TA, Wagner JJ, Martin LA, MorishitaW, Kirov SA & Lenz RA (1996) Retrograde signallingin depolarization-induced suppression of inhibition inrat hippocampal CA1 cells. J Physiol 496, 197–209.71 Kawamura Y, Fukaya M, Maejima T, Yoshida T, MiuraE, Watanabe M, Ohno-Shosaku T & Kano M (2006) TheCB1 cannabinoid receptor is the major cannabinoidreceptor at excitatory presynaptic sites in the hippocam-pus and cerebellum. J Neurosci 26, 2991–3001.72 Hoffman AF & Lupica CR (2000) Mechanisms of can-nabinoid inhibition of GABA(A) synaptic transmissionin the hippocampus. J Neurosci 20, 2470–2479.73 Chevaleyre V & Castillo PE (2003) HeterosynapticLTD of hippocampal GABAergic synapses. A novelrole of endocannabinoids in regulating excitability.Neuron 38, 461–472.74 Marsicano G, Goodenough S, Monory K, HermannH, Eder M, Cannich A, Azad SC, Cascio MG, Gut-ierrez SO, van der Stelt M et al. (2003) CB1 cannabi-noid receptors and on-demand defense againstexcitotoxicity. Science 302, 84–88.75 Monory K, Massa F, Egertova M, Eder M, BlaudzunH, Westenbroek R, Kelsch W, Jacob W, Marsch R,Ekker M et al. (2006) The endocannabinoid systemcontrols key epileptogenic circuits in the hippocampus.Neuron 51, 455–466.76 Chen K, Ratzliff A, Hilgenberg L, Gulyas A, FreundTF, Smith M, Dinh TP, Piomelli D, Mackie K & Sol-tesz I (2003) Long-term plasticity of endocannabinoidsignaling induced by developmental febrile seizures.Neuron 39, 599–611.77 Chen K, Neu A, Howard AL, Foldy C, Echegoyen J,Hilgenberg L, Smith M, Mackie K & Soltesz I (2007)Prevention of plasticity of endocannabinoid signalinginhibits persistent limbic hyperexcitability caused bydevelopmental seizures. J Neurosci 27, 46–58.78 Navarrete M & Araque A (2008) Endocannabinoidsmediate neuron-astrocyte communication. Neuron 57,883–893.79 Gebremedhin D, Lange AR, Campbell WB, Hillard CJ& Harder DR (1999) Cannabinoid CB1 receptor of catcerebral arterial muscle functions to inhibit L-typeCa2+ channel current. Am J Physiol 276, H2085–H2093.80 Wagner JA, Jarai Z, Batkai S & Kunos G (2001)Hemodynamic effects of cannabinoids: coronary andcerebral vasodilation mediated by cannabinoid CB1receptors. Eur J Pharmacol 423, 203–210.81 Hillard CJ (2000) Endocannabinoids and vascularfunction. J Pharmacol Exp Ther 294, 27–32.82 Mathew RJ, Wilson WH & Davis R (2003) Posturalsyncope after marijuana: a transcranial Doppler studyof the hemodynamics. Pharmacol Biochem Behav 75,309–318.83 MacGregor DG, Carswell HVO, Graham DI, McCul-loch J & Macrae IM (2000) Impaired cerebral autore-gulation 24 h after induction of transient unilateralfocal ischaemia in the rat. Eur J Neurosci 12, 58–66.84 Golech SA, McCarron RM, Chen Y, Bembry J, LenzF, Mechoulam R, Shohami E & Spatz M (2004)Human brain endothelium: coexpression and functionof vanilloid and endocannabinoid receptors. Brain ResMol Brain Res 132, 87–92.85 McCollum L, Howlett AC & Mukhopadhyay S (2007)Anandamide-mediated CB1 ⁄ CB2 cannabinoid recep-tor-independent nitric oxide production in rabbit aorticendothelial cells. J Pharmacol Exp Ther 321, 930–937.D. E. Pellegrini-Giampietro et al. The endocannabinoid system in cerebral ischemiaFEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation ª 2008 FEBS 11[...]... Regulation of PI3K ⁄ Akt ⁄ GSK-3 pathway by cannabinoids in the brain J Neurochem 102, 1105–1114 93 Molina-Holgado E, Vela JM, Arevalo-Martin A, Almazan G, Molina-Holgado F, Borrell J & Guaza C (2002) Cannabinoids promote oligodendrocyte progenitor survival: Involvement of cannabinoid receptors and phosphatidylinositol-3 kinase ⁄ Akt signaling J Neurosci 22, 9742–9753 94 Molina-Holgado F, Pinteaux E,... Neuroprotective effects of the synthetic cannabinoid HU-210 in primary cortical neurons are mediated by phosphatidylinositol 3-kinase ⁄ AKT signaling Mol Cell Neurosci 28, 189– 194 95 Khaspekov LG, Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G & Lutz B (2004) Involvement of brain- derived neurotrophic factor in cannabinoid 12 96 97 98 99 100 101 102 103 104 105 receptor-dependent protection against excitotoxicity... [(4,5-dihydro-2-methyl-4(4morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6Hpyrrolo[3,2,1ij]quinolin-6-one]-induced hypothermia J Pharmacol Exp Ther 301, 963–968 90 Chan GCK, Hinds TR, Impey S & Storm DR (1998) Hippocampal neurotoxicity of Delta(9)-tetrahydrocannabinol J Neurosci 18, 5322–5332 91 Gomez del Pulgar T, Velasco G & Guzman M (2000) The CB1 cannabinoid receptor is coupled to the activation of protein kinase B ⁄... Acad Sci USA 105, 2699–2704 Bisogno T & Di Marzo V (2008) The role of the endocannabinoid system in Alzheimer’s disease: facts and hypotheses Curr Pharm Des 14, 2299–3305 Kim SR, Chung YC, Chung ES, Park KW, Won SY, Bok E, Park ES & Jin BK (2007) Roles of transient receptor potential vanilloid subtype 1 and cannabinoid type 1 receptors in the brain: neuroprotection versus neurotoxicity Mol Neurobiol 35,... SS & Makriyannis A (2006) Targeting the endocannabinoid system in treating brain disorders Expert Opin Investig Drugs 15, 351–365 Franklin A, Parmentier-Batteur S, Walter L, Greenberg DA & Stella N (2003) Palmitoylethanolamide increases after focal cerebral ischemia and potentiates microglial cell motility J Neurosci 23, 7767–7775 FEBS Journal 276 (2009) 2–12 ª 2008 The Authors Journal compilation... (2001) Cannabinoid-receptor-independent cell signalling by N-acylethanolamines Biochem J 360, 67–75 Maccarrone M, Lorenzon T, Bari M, Melino G & Finazzi-Agro A (2000) Anandamide induces apoptosis in human cells via vanilloid receptors – evidence for a protective role of cannabinoid receptors J Biol Chem 275, 31938–31945 Grant ER, Dubin AE, Zhang SP, Zivin RA & Zhong Z (2002) Simultaneous intracellular.. .The endocannabinoid system in cerebral ischemia D E Pellegrini-Giampietro et al 86 Ellis EF, Moore SF & Willoughby KA (1995) Anandamide and delta 9-THC dilation of cerebral arterioles is blocked by indomethacin Am J Physiol 269, H1859– H1864 87 Poblete IM, Orliac ML, Briones R, Adler-Graschinsky E & Huidobro-Toro JP (2005) Anandamide elicits an acute release of nitric oxide through endothelial... excitotoxicity Eur J Neurosci 19, 1691–1698 Chen YQ & Buck J (2000) Cannabinoids protect cells from oxidative cell death: a receptor-independent mechanism J Pharmacol Exp Ther 293, 807–812 Marsicano G, Moosmann B, Hermann H, Lutz B & Behl C (2002) Neuroprotective properties of cannabinoids against oxidative stress: role of the cannabinoid receptor CB1 J Neurochem 80, 448–456 Berdyshev EV, Schmid PC, Krebsbach... Simultaneous intracellular calcium and sodium flux imaging in human vanilloid receptor 1 (VR1)-transfected human embryonic kidney cells: a method to resolve ionic dependence of VR1-mediated cell death J Pharmacol Exp Ther 300, 9–17 Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B & Mackie K (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current Proc Natl Acad Sci USA 105,... activation in the rat arterial mesenteric bed J Physiol 568, 539–551 88 Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sorgard M, Di Marzo V, Julius D & Hogestatt ED (1999) Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide Nature 400, 452–457 89 Rawls SM, Cabassa J, Geller EB & Adler MW (2002) CB1 receptors in the preoptic anterior hypothalamus regulate win 55212-2 . MINIREVIEW Post-ischemic brain damage: the endocannabinoid system in the mechanisms of neuronal death Domenico E. Pellegrini-Giampietro1,. addressed the role of the endocannabinoid system in stroke and in the mechanisms of post-ischemic neuronal death (Table 1). To this end, models of focal
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