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URB597 and the Cannabinoid WIN55,212-2 Reduce Behavioral and Neurochemical Deficits Induced by MPTP in Mice: Possible Role of Redox Modulation and NMDA Receptors

Abstract

Several physiological events in the brain are regulated by the endocannabinoid system (ECS). While synthetic cannabinoid receptor (CBr) agonists such as WIN55,212-2 act directly on CBr, agents like URB597, a fatty acid amide hydrolase (FAAH) inhibitor, induce a more “physiological” activation of CBr by increasing the endogenous levels of the endocannabinoid anandamide (AEA). Herein, we compared the pre- and post-treatment efficacy of URB597 and WIN55,212-2 on different endpoints evaluated in the toxic model produced by the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice. MPTP (40 mg/kg, s.c., single injection) decreased locomotor activity, depleted the striatal and nigral levels of dopamine (DA), augmented the levels of lipid peroxidation and protein carbonylation in both regions, decreased the striatal protein levels of tyrosine hydroxylase, and increased the striatal protein content of the subunit 1 (NR1) of the N-methyl-d-aspartate receptor (NMDAr). Both URB597 (0.3 mg/kg, i.p., once a day) and WIN55,212-2 (10 μg/kg, i.p., twice a day), administered for five consecutive days, either before or after the MPTP injection, prevented the alterations elicited by MPTP and downregulated NMDAr. Our results support a modulatory role of the ECS on the toxic profile exerted by MPTP in mice via the stimulation of antioxidant activity and the induction of NMDAr downregulation and hypofunction, and favor the stimulation of CBr as an effective experimental therapeutic strategy.

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Acknowledgements

We would like to thank Salvador Monje for his technical support.

Funding

This work was supported by CONACyT-TUBITAK Grant 265991 (A.S.).

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Correspondence to Esperanza García or Abel Santamaría.

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All procedures with mice were carried out strictly according to the local guidelines (Norma Oficial Mexicana NOM-062-ZOO-2001) for the use and care of laboratory animals as well as the “Guidelines for the Use of Animals in Neuroscience Research” from the Society of Neuroscience. The experiments were approved by the Ethics Committee of the INNN.

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The authors declare that they have no conflict of interest.

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Escamilla-Ramírez, A., García, E., Palencia-Hernández, G. et al. URB597 and the Cannabinoid WIN55,212-2 Reduce Behavioral and Neurochemical Deficits Induced by MPTP in Mice: Possible Role of Redox Modulation and NMDA Receptors. Neurotox Res 31, 532–544 (2017). https://doi.org/10.1007/s12640-016-9698-1

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  • DOI: https://doi.org/10.1007/s12640-016-9698-1

Keywords

  • MPTP toxic model
  • Oxidative stress
  • Neurochemical deficits
  • Endocannabinoid system
  • Cannabinoid receptor agonists
  • NMDAr hypofunction