The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model

Diana Fernández-Suárez, Marta Celorrio, José Ignacio Riezu-Boj, Ana Ugarte, Rodrigo Pacheco, Hugo González, Julen Oyarzabal, Cecilia J. Hillard, Rafael Franco, María S. Aymerich

Resultado de la investigación: Article

40 Citas (Scopus)

Resumen

Changes in cannabinoid receptor expression and concentration of endocannabinoids have been described in Parkinson's disease; however, it remains unclear whether they contribute to, or result from, the disease process. To evaluate whether targeting the endocannabinoid system could provide potential benefits in the treatment of the disease, the effect of a monoacylglycerol lipase inhibitor that prevents degradation of 2-arachidonyl-glycerol was tested in mice treated chronically with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp). Chronic administration of the compound, JZL184 (8mg/kg), prevented MPTPp-induced motor impairment and preserved the nigrostriatal pathway. Furthermore, none of the hypokinetic effects associated with cannabinoid receptor agonism were observed. In the striatum and substantia nigra pars compacta, MPTPp animals treated with JZL184 exhibited astroglial and microglial phenotypic changes that were accompanied by increases in TGFβ messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in β-catenin translocation to the nucleus, implicating the Wnt/catenin pathway. Together, these results demonstrate a potent neuroprotective effect of JZL184 on the nigrostriatal pathway of parkinsonian animals, likely involving restorative astroglia and microglia activation and the release of neuroprotective and antiinflammatory molecules.

Idioma originalEnglish
Páginas (desde-hasta)2603-2616
Número de páginas14
PublicaciónNeurobiology of Aging
Volumen35
N.º11
DOI
EstadoPublished - 1 ene 2014

Huella dactilar

Monoacylglycerol Lipases
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Neuroglia
Phenotype
Catenins
Cannabinoid Receptors
Endocannabinoids
Probenecid
Messenger RNA
Wnt Signaling Pathway
Nerve Growth Factors
Microglia
Neuroprotective Agents
Astrocytes
Parkinson Disease
Anti-Inflammatory Agents
JZL 184
Proteins

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Citar esto

Fernández-Suárez, D., Celorrio, M., Riezu-Boj, J. I., Ugarte, A., Pacheco, R., González, H., ... Aymerich, M. S. (2014). The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. Neurobiology of Aging, 35(11), 2603-2616. https://doi.org/10.1016/j.neurobiolaging.2014.05.021
Fernández-Suárez, Diana ; Celorrio, Marta ; Riezu-Boj, José Ignacio ; Ugarte, Ana ; Pacheco, Rodrigo ; González, Hugo ; Oyarzabal, Julen ; Hillard, Cecilia J. ; Franco, Rafael ; Aymerich, María S. / The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. En: Neurobiology of Aging. 2014 ; Vol. 35, N.º 11. pp. 2603-2616.
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title = "The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model",
abstract = "Changes in cannabinoid receptor expression and concentration of endocannabinoids have been described in Parkinson's disease; however, it remains unclear whether they contribute to, or result from, the disease process. To evaluate whether targeting the endocannabinoid system could provide potential benefits in the treatment of the disease, the effect of a monoacylglycerol lipase inhibitor that prevents degradation of 2-arachidonyl-glycerol was tested in mice treated chronically with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp). Chronic administration of the compound, JZL184 (8mg/kg), prevented MPTPp-induced motor impairment and preserved the nigrostriatal pathway. Furthermore, none of the hypokinetic effects associated with cannabinoid receptor agonism were observed. In the striatum and substantia nigra pars compacta, MPTPp animals treated with JZL184 exhibited astroglial and microglial phenotypic changes that were accompanied by increases in TGFβ messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in β-catenin translocation to the nucleus, implicating the Wnt/catenin pathway. Together, these results demonstrate a potent neuroprotective effect of JZL184 on the nigrostriatal pathway of parkinsonian animals, likely involving restorative astroglia and microglia activation and the release of neuroprotective and antiinflammatory molecules.",
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Fernández-Suárez, D, Celorrio, M, Riezu-Boj, JI, Ugarte, A, Pacheco, R, González, H, Oyarzabal, J, Hillard, CJ, Franco, R & Aymerich, MS 2014, 'The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model', Neurobiology of Aging, vol. 35, n.º 11, pp. 2603-2616. https://doi.org/10.1016/j.neurobiolaging.2014.05.021

The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model. / Fernández-Suárez, Diana; Celorrio, Marta; Riezu-Boj, José Ignacio; Ugarte, Ana; Pacheco, Rodrigo; González, Hugo; Oyarzabal, Julen; Hillard, Cecilia J.; Franco, Rafael; Aymerich, María S.

En: Neurobiology of Aging, Vol. 35, N.º 11, 01.01.2014, p. 2603-2616.

Resultado de la investigación: Article

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T1 - The monoacylglycerol lipase inhibitor JZL184 is neuroprotective and alters glial cell phenotype in the chronic MPTP mouse model

AU - Fernández-Suárez, Diana

AU - Celorrio, Marta

AU - Riezu-Boj, José Ignacio

AU - Ugarte, Ana

AU - Pacheco, Rodrigo

AU - González, Hugo

AU - Oyarzabal, Julen

AU - Hillard, Cecilia J.

AU - Franco, Rafael

AU - Aymerich, María S.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Changes in cannabinoid receptor expression and concentration of endocannabinoids have been described in Parkinson's disease; however, it remains unclear whether they contribute to, or result from, the disease process. To evaluate whether targeting the endocannabinoid system could provide potential benefits in the treatment of the disease, the effect of a monoacylglycerol lipase inhibitor that prevents degradation of 2-arachidonyl-glycerol was tested in mice treated chronically with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp). Chronic administration of the compound, JZL184 (8mg/kg), prevented MPTPp-induced motor impairment and preserved the nigrostriatal pathway. Furthermore, none of the hypokinetic effects associated with cannabinoid receptor agonism were observed. In the striatum and substantia nigra pars compacta, MPTPp animals treated with JZL184 exhibited astroglial and microglial phenotypic changes that were accompanied by increases in TGFβ messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in β-catenin translocation to the nucleus, implicating the Wnt/catenin pathway. Together, these results demonstrate a potent neuroprotective effect of JZL184 on the nigrostriatal pathway of parkinsonian animals, likely involving restorative astroglia and microglia activation and the release of neuroprotective and antiinflammatory molecules.

AB - Changes in cannabinoid receptor expression and concentration of endocannabinoids have been described in Parkinson's disease; however, it remains unclear whether they contribute to, or result from, the disease process. To evaluate whether targeting the endocannabinoid system could provide potential benefits in the treatment of the disease, the effect of a monoacylglycerol lipase inhibitor that prevents degradation of 2-arachidonyl-glycerol was tested in mice treated chronically with probenecid and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTPp). Chronic administration of the compound, JZL184 (8mg/kg), prevented MPTPp-induced motor impairment and preserved the nigrostriatal pathway. Furthermore, none of the hypokinetic effects associated with cannabinoid receptor agonism were observed. In the striatum and substantia nigra pars compacta, MPTPp animals treated with JZL184 exhibited astroglial and microglial phenotypic changes that were accompanied by increases in TGFβ messenger RNA expression and in glial cell-derived neurotrophic factor messenger RNA and protein levels. JZL184 induced an increase in β-catenin translocation to the nucleus, implicating the Wnt/catenin pathway. Together, these results demonstrate a potent neuroprotective effect of JZL184 on the nigrostriatal pathway of parkinsonian animals, likely involving restorative astroglia and microglia activation and the release of neuroprotective and antiinflammatory molecules.

KW - Astroglia

KW - Endocannabinoid system

KW - JZL184

KW - Microglia

KW - Monoacylglycerol lipase

KW - Neuroprotection

KW - Parkinson's disease

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JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

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