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Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats.

Abstract

Brain slices from 7-d-old Wistar rats were exposed to oxygen-glucose deprivation (OGD) for 30 min. OGD slices were incubated with vehicle or with the CB1/CB2 cannabinoid agonist WIN55212 (50 microM), the CB1 agonist arachidonyl-2-chloroethylamide (ACEA) (50 microM), or the CB2 agonist JW133 (50 microM), alone or combined with the CB1 and CB2 receptor antagonist SR 141716 (50 microM) or SR 144528 (50 microM), respectively. Neuronal damage was assessed by histologic analysis and spectrophotometric determination of lactate dehydrogenase (LDH) efflux into the incubation medium. Additionally, medium glutamate levels were determined by high-performance liquid chromatography (HPLC) and those of tumor necrosis factor alpha (TNF-alpha) by enzyme-linked immunosorbent assay. Finally, inducible nitric oxide synthase (iNOS) and CB1/CB2 receptor expression were determined in slices homogenate by Western blot. Both CB1 and CB2 receptors were expressed in slices. OGD increased CB1 expression, cellular damage, LDH efflux, glutamate and TNF-alpha release, and inducible nitric oxide synthase (iNOS) expression; WIN55212 inhibited all these actions. SR141716 and SR144528 inhibited the effect of R(+)-WIN-55212-2 (WIN), as well as the reduction of LDH efflux by ACEA and JW133, respectively. In conclusion, WIN55212 afforded robust neuroprotection in the forebrain slices exposed to OGD, by acting on glutamatergic excitotoxicity, TNF-alpha release, and iNOS expression; this neuroprotective effect seemed to be mediated by CB1 and CB2 receptors.

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  • Authors+Show Affiliations

    ,

    Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.

    , , , , ,

    Source

    Pediatric research 60:2 2006 Aug pg 169-73

    MeSH

    Anaerobiosis
    Animals
    Animals, Newborn
    Arachidonic Acids
    Benzoxazines
    Brain
    Brain Chemistry
    Brain Ischemia
    Cannabinoid Receptor Agonists
    Cannabinoids
    Disease Models, Animal
    Hypoxia, Brain
    L-Lactate Dehydrogenase
    Morpholines
    Naphthalenes
    Neuroprotective Agents
    Nitric Oxide Synthase Type II
    Piperidines
    Pyrazoles
    Rats
    Rats, Wistar
    Receptor, Cannabinoid, CB1
    Receptor, Cannabinoid, CB2
    Rimonabant
    Tumor Necrosis Factor-alpha

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16864698

    Citation

    Fernández-López, David, et al. "Characterization of the Neuroprotective Effect of the Cannabinoid Agonist WIN-55212 in an in Vitro Model of Hypoxic-ischemic Brain Damage in Newborn Rats." Pediatric Research, vol. 60, no. 2, 2006, pp. 169-73.
    Fernández-López D, Martínez-Orgado J, Nuñez E, et al. Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res. 2006;60(2):169-73.
    Fernández-López, D., Martínez-Orgado, J., Nuñez, E., Romero, J., Lorenzo, P., Moro, M. A., & Lizasoain, I. (2006). Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatric Research, 60(2), pp. 169-73.
    Fernández-López D, et al. Characterization of the Neuroprotective Effect of the Cannabinoid Agonist WIN-55212 in an in Vitro Model of Hypoxic-ischemic Brain Damage in Newborn Rats. Pediatr Res. 2006;60(2):169-73. PubMed PMID: 16864698.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. AU - Fernández-López,David, AU - Martínez-Orgado,José, AU - Nuñez,Estefanía, AU - Romero,Julián, AU - Lorenzo,Pedro, AU - Moro,Maria Angeles, AU - Lizasoain,Ignacio, PY - 2006/7/26/pubmed PY - 2006/9/26/medline PY - 2006/7/26/entrez SP - 169 EP - 73 JF - Pediatric research JO - Pediatr. Res. VL - 60 IS - 2 N2 - Brain slices from 7-d-old Wistar rats were exposed to oxygen-glucose deprivation (OGD) for 30 min. OGD slices were incubated with vehicle or with the CB1/CB2 cannabinoid agonist WIN55212 (50 microM), the CB1 agonist arachidonyl-2-chloroethylamide (ACEA) (50 microM), or the CB2 agonist JW133 (50 microM), alone or combined with the CB1 and CB2 receptor antagonist SR 141716 (50 microM) or SR 144528 (50 microM), respectively. Neuronal damage was assessed by histologic analysis and spectrophotometric determination of lactate dehydrogenase (LDH) efflux into the incubation medium. Additionally, medium glutamate levels were determined by high-performance liquid chromatography (HPLC) and those of tumor necrosis factor alpha (TNF-alpha) by enzyme-linked immunosorbent assay. Finally, inducible nitric oxide synthase (iNOS) and CB1/CB2 receptor expression were determined in slices homogenate by Western blot. Both CB1 and CB2 receptors were expressed in slices. OGD increased CB1 expression, cellular damage, LDH efflux, glutamate and TNF-alpha release, and inducible nitric oxide synthase (iNOS) expression; WIN55212 inhibited all these actions. SR141716 and SR144528 inhibited the effect of R(+)-WIN-55212-2 (WIN), as well as the reduction of LDH efflux by ACEA and JW133, respectively. In conclusion, WIN55212 afforded robust neuroprotection in the forebrain slices exposed to OGD, by acting on glutamatergic excitotoxicity, TNF-alpha release, and iNOS expression; this neuroprotective effect seemed to be mediated by CB1 and CB2 receptors. SN - 0031-3998 UR - https://www.unboundmedicine.com/medline/citation/16864698/Characterization_of_the_neuroprotective_effect_of_the_cannabinoid_agonist_WIN_55212_in_an_in_vitro_model_of_hypoxic_ischemic_brain_damage_in_newborn_rats_ L2 - http://dx.doi.org/10.1203/01.pdr.0000228839.00122.6c DB - PRIME DP - Unbound Medicine ER -