Original article URB597 reduces biochemical, behavioral and morphological alterations in two neurotoxic models in rats Marisol Maya-López a,1 , Hipolito A. Ruiz-Contreras a,b,1 , María de Jesús Negrete-Ruíz a,c , Julián Elías Martínez-Sánchez a,d , Juan Benítez-Valenzuela a,e , Ana Laura Colín-González a , Juana Villeda-Hernández f , Laura Sánchez-Chapul g , Carmen Parra-Cid h , Edgar Rangel-López a, *, Abel Santamaría a, * a Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico b Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico c Facultad de Ciencias Químicas, Universidad de Colima, Colima, Mexico d Facultad de Medicina, Universidad de Colima, Colima, Mexico e Facultad de Medicina, Universidad Autónoma de Sinaloa, Sinaloa, Mexico f Laboratorio de Patología Experimental, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico g Laboratorio de Bioquímica, Instituto Nacional de Rehabilitación, Mexico City, Mexico h Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación, S.S.A., Mexico City, Mexico A R T I C L E I N F O Article history: Received 15 November 2016 Received in revised form 10 January 2017 Accepted 19 January 2017 Keywords: Neurodegeneration Mitochondrial energy depletion Oxidative damage Endocannabinoid system Fatty acid amide hydrolase inhibition URB597 Neuromodulation A B S T R A C T Background: URB597 is a compound largely linked to the inhibition of fatty acid amide hydrolase (FAAH), an enzyme responsible for the metabolic degradation of the endocannabinoid anandamide (AEA). Despite this pharmacological property accounts for its modulatory profile demonstrated in some neurotoxic paradigms, the possible protective properties of this agent have been poorly investigated, and deserve exploration in different neurotoxic models. In this study, we explored the effects of URB597 on oxidative damage to lipids and other major endpoints of toxicity in two neurotoxic models in vivo in rats (the first one produced by the mitochondrial neurotoxin 3-nitropropionic acid [3-NP], and the other generated by the striatal injection of the pro-oxidant toxin 6-hydroxidopamine [6-OHDA]) in order to provide further supporting evidence of its modulatory profile. Methods: Male Wistar adult rats were treated for 5 or 7 consecutive days with URB597 (0.3 mg/kg, i.p.) and simultaneously exposed to three injections of 3-NP (30 mg/kg, i.p.) or a single intrastriatal infusion of 6-OHDA (0.02 mg/2 ml), respectively. Twenty four hours after all treatments were administered, lipid peroxidation was measured in the striatum of 3-NP-treated rats, and in the midbrain of 6-OHDA-treated rats. Motor skills and histological assessment in the striatum were also evaluated in 3-NP-treated rats 6 and 7 days after the last drug administration, respectively; whereas apomorphine-induced circling behavior and tyrosine hydroxylase immunolocalization in the striatum and substantia nigra were investigated 21 and 22 days after the last drug infusion, respectively. Results: URB597 prevented the oxidative damage to lipids induced by 3-NP in the striatum, and this effect could account for the attenuation of motor deficits in this model. Attenuation of motor disturbances induced by URB597 in both models was associated with the morphological preservation of the striatum in the 3-NP model and the partial preservation of tyrosine hydroxylase in the 6-OHDA model in the SNpc and striatum. Conclusion: The modulatory actions exerted by URB597 in both toxic models support its potential against toxic conditions implying motor and neurochemical alterations linked to energy depletion, excitotoxicity and oxidative stress. Although most of these effects could be attributable to its action on FAAH and further AEA accumulation, in light of our present findings other properties are suggested. © 2017 Elsevier Masson SAS. All rights reserved. * Corresponding authors at: Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, Insurgentes Sur 3877, Ciudad de México 14269, México. E-mail address: absada@yahoo.com (A. Santamaría). 1 These authors equally contributed to this work. http://dx.doi.org/10.1016/j.biopha.2017.01.116 0753-3322/© 2017 Elsevier Masson SAS. All rights reserved. Biomedicine & Pharmacotherapy 88 (2017) 745–753 Available online at ScienceDirect www.sciencedirect.com