POTENTIAL OXIDATION OF 2-AG BY COX-2 ENHANCES MALONATE TOXICITY IN THE STRIATUM: RELEVANCE FOR CANNABINOID TREATMENTS IN HUNTINGTON’S DISEASE (Comunicazione a convegno)

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  • POTENTIAL OXIDATION OF 2-AG BY COX-2 ENHANCES MALONATE TOXICITY IN THE STRIATUM: RELEVANCE FOR CANNABINOID TREATMENTS IN HUNTINGTON’S DISEASE (Comunicazione a convegno) (literal)
Anno
  • 2010-01-01T00:00:00+01:00 (literal)
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  • Onintza Sagredo, María Ruth Pazos, Tiziana Bisogno, Fabiana Piscitelli, Stefania Petrosino, Mariluz Hernández, Vincenzo Di Marzo and Javier Fernández-Ruiz (2010)
    POTENTIAL OXIDATION OF 2-AG BY COX-2 ENHANCES MALONATE TOXICITY IN THE STRIATUM: RELEVANCE FOR CANNABINOID TREATMENTS IN HUNTINGTON’S DISEASE
    in ICRS 20th Symposium, Lund, Sweden
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Onintza Sagredo, María Ruth Pazos, Tiziana Bisogno, Fabiana Piscitelli, Stefania Petrosino, Mariluz Hernández, Vincenzo Di Marzo and Javier Fernández-Ruiz (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#descrizioneSinteticaDelProdotto
  • The cannabinoid signaling system encompasses the CB2 receptor, which protects striatal neurons from the apoptotic death caused by the local administration of malonate, a rat model of Huntington’s disease (HD). In the present study, we investigated if endocannabinoids provide tonic neuroprotection in this HD model, by examining first the effect of O-3841, an inhibitor of diacylglycerol lipases (DAGLs), the enzymes that catalyse the biosynthesis of 2-arachidonoyl-glycerol (2-AG). The local administration of O-3841 produced a significant reduction in the striatal levels of 2-AG in animals lesioned with malonate, without affecting the levels of anandamide. Neither anandamide nor 2-AG were altered by the lesion of the striatum with malonate alone. Given the neuroprotective properties previously described for 2-AG, a reduction of its levels by O-3841 was expected to enhance the magnitude of malonate-induced lesion. However, we observed that, rather than being harmful, the inhibitor enhanced the survival of striatal neurons since it partially attenuated the malonate-induced GABA and BDNF deficits, whilst reducing the number of dead neurons and glial activation. By contrast, OMDM169, an inhibitor of monoacylglycerol lipase (MAGL), which maintained elevated 2-AG levels, was unable to protect striatal neurons, and it even aggravated striatal damage. These data agree with previous information indicating that 2-AG may be neurotoxic under certain circumstances through its transformation into prostaglandin glyceryl esters by the action of cyclooxygenase-2 (COX-2). Indeed, we found here that COX-2 is induced in vivo in the striatum 24 hours after the lesion, a fact also reproduced in vitro in cultured M-213 cells exposed to malonate. In vivo, using a sensitive ESI-IT-ToF LC-MS technique, we could not detect the major 2-AG oxygenated metabolite, prostaglandin E2 glyceryl ester (PGE2-Gs), presumably because the generation of this compound is strictly localised to the lesioned areas, thus reaching levels (<0.1 pmol/g tissue) that cannot be detected in the whole striatum with our method. Interestingly, however, the treatment of M-213 cells with malonate combined with the inhibitor of DAGL O-3841 attenuated cell death, whereas the blockade of MAGL with OMDM169 caused the opposite effect as in the in vivo experiments. We are presently analyzing whether both effects were accompanied by the expected reduction or increase in the generation of PGE2-Gs, respectively. The lesion with malonate also caused up-regulation of inducible nitric oxide synthase in the striatum, as well as a marked decrease in nuclear receptors with anti-inflammatory action, like PPAR-± and –³, this latter effect being partially corrected by the treatment with O-3841. In summary, the inhibition of 2-AG biosynthesis is neuroprotective in rats lesioned with malonate, possibly because this effect might have counteracted some pro-neuroinflammatory actions of 2-AG. Supported by MEC (SAF2009-11847), CIBERNED (CB06/05/0089) and CAM (S-SAL- 0261/2006). Authors are indebted to Yolanda García-Movellán for administrative support. (literal)
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  • 1Departamento de Bioquímica y Biología Molecular and CIBERNED, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain; 2Endocannabinoid Research Group, Institute of Biomolecular Chemistry, Consiglio Nazionale delle Ricerche, Via Campi Flegrei 34, Comprensorio Olivetti, 80078 Pozzuoli, Naples, Italy (literal)
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  • POTENTIAL OXIDATION OF 2-AG BY COX-2 ENHANCES MALONATE TOXICITY IN THE STRIATUM: RELEVANCE FOR CANNABINOID TREATMENTS IN HUNTINGTON’S DISEASE (literal)
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