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
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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.
KeywordsMPTP toxic model Oxidative stress Neurochemical deficits Endocannabinoid system Cannabinoid receptor agonists NMDAr hypofunction
We would like to thank Salvador Monje for his technical support.
This work was supported by CONACyT-TUBITAK Grant 265991 (A.S.).
Compliance with Ethical Standards
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.
Conflict of Interest
The authors declare that they have no conflict of interest.
- Aguirre JA, Kehr J, Yoshitake T, Liu FL, Rivera A, Fernandez-Espinola S, Fuxe K (2005) Protection but maintained dysfunction of nigral dopaminergic nerve cell bodies and striatal dopaminergic terminals in MPTP-lesioned mice after acute treatment with the mGluR5 antagonist MPEP. Brain Res 1033:216–220CrossRefPubMedGoogle Scholar
- Burns RS, Chiueh CC, Markey SP, Ebert MH, Jacobowitz DM, Kopin IJ (1983) A primate model of parkinsonism: selective destruction of dopaminergic neurons in the pars compacta of the substantia nigra by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Proc Natl Acad Sci U S A 80:4546–4550CrossRefPubMedPubMedCentralGoogle Scholar
- Celorrio M, Fernández-Suárez D, Rojo-Bustamante E, Echeverry-Alzate V, Ramírez MJ, Hillard CJ, López-Moreno JA, Maldonado R, Oyarzábal J, Franco R, Aymerich MS (2016) Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson’s disease. Brain Behav Immun 57:94–105CrossRefPubMedGoogle Scholar
- Colin-Gonzalez AL, Orozco-Ibarra M, Chanez-Cardenas ME, Rangel-Lopez E, Santamaria A, Pedraza-Chaverri J, Barrera-Oviedo D, Maldonado PD (2013) Heme oxygenase-1 (HO-1) upregulation delays morphological and oxidative damage induced in an excitotoxic/pro-oxidant model in the rat striatum. Neuroscience 231:91–101CrossRefPubMedGoogle Scholar
- Garcia E, Santana-Martinez R, Silva-Islas CA, Colín-Gonzalez AL, Galván-Arzate S, Heras Y, Maldonado PD, Sotelo J, Santamaría A (2014) S-allyl cysteine protects against MPTP-induced striatal and nigral oxidative neurotoxicity in mice: participation of Nrf2. Free Radic Res 48:159–167CrossRefPubMedGoogle Scholar
- Johnston TH, Huot P, Fox SH, Wakefield JD, Sykes KA, Bartolini WP, Milne GT, Pearson JP, Brotchie JM (2011) Fatty acid amide hydrolase (FAAH) inhibition reduces L-3,4-dihydroxyphenylalanine-induced hyperactivity in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned non-human primate model of Parkinson’s disease. J Pharmacol Exp Ther 336:423–430CrossRefPubMedGoogle Scholar
- Lastres-Becker I, Cebeira M, de Ceballos ML, Zeng BY, Jenner P, Ramos JA, Fernández-Ruiz JJ (2001) Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson’s syndrome and of MPTP-treated marmosets. Eur J Neurosci 14:1827–1832CrossRefPubMedGoogle Scholar
- Ma J, Choi B-R, Chung C-H, Min SS, Jeon WK, Han J-S (2014) Chronic brain inflammation causes a reduction in GluN2A and GluN2B subunits of NMDA receptors and an increase in the phosphorylation of mitogen-activated protein kinases in the hippocampus. Mol Brain 7:33CrossRefPubMedPubMedCentralGoogle Scholar
- Mechoulam R, Fride E (1995) In: Pertwee R (ed) The unpaved road to the endogenous brain cannabinoid ligands, the anandamides in “Cannabinoid Receptors”. Academic Press, London, pp 233–258Google Scholar
- Mogi M, Togari A, Ogawa M, Ikeguchi K, Shizuma N, Fan D, Nakano I, Nagatsu T (1998) Effects of repeated systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to mice on interleukin-1beta and nerve growth factor in the striatum. Neurosci Lett 250:25–28CrossRefPubMedGoogle Scholar
- Price DA, Martinez AA, Seillier A, Koek W, Acosta Y, Fernandez E, Strong JR, Lutz B, Marsicano G, Roberts JL, Giuffrida A (2009) WIN55,212-2, a cannabinoid receptor agonist, protects against nigrostriatal cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease. Eur J Neurosci 29:2177–2186CrossRefPubMedPubMedCentralGoogle Scholar
- Russo R, Loverme J, La Rana G, Compton TR, Parrott J, Duranti A, Tontini A, Mor M, Tarzia G, Calignano A, Piomelli D (2007) The fatty-acid amide hydrolase inhibitor URB597 (cyclohexyl carbamic acid 3′-carbamoyl-biphenyl-3-yl ester) reduces neuropathic pain after oral administration in mice. J Pharmacol Exp Ther 322:236–242CrossRefPubMedGoogle Scholar
- Tatem KS, Quinn JL, Phadke A, Yu Q, Gordish-Dressman H, Nagaraju K (2014) Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases. J Vis Exp 91:51785Google Scholar