URB597 reduces biochemical, behavioral and morphological alterations in two neurotoxic models in rats.
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 (0.3mg/kg, i.p.) and simultaneously exposed to three injections of 3-NP (30mg/kg, i.p.) or a single intrastriatal infusion of 6-OHDA (0.02mg/2μl), 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 7days 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 22days 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.


CONCLUSIONS
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.
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
Marisol
M
Maya-López
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico; Facultad de Ciencias, Universidad Nacional Autónoma de México, Mexico City, Mexico.
Hipolito A
HA
Ruiz-Contreras
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico; Facultad de Ciencias Químicas, Universidad de Colima, Colima, Mexico.
María
M
de Jesús Negrete-Ruíz
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico; Facultad de Medicina, Universidad de Colima, Colima, Mexico.
Julián Elías
JE
Martínez-Sánchez
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico; Facultad de Medicina, Universidad Autónoma de Sinaloa, Sinaloa, Mexico.
Juan
J
Benítez-Valenzuela
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
Ana Laura
AL
Colín-González
Laboratorio de Patología Experimental, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
Juana
J
Villeda-Hernández
Laboratorio de Bioquímica, Instituto Nacional de Rehabilitación, Mexico City, Mexico.
Laura
L
Sánchez-Chapul
Unidad de Ingeniería de Tejidos, Terapia Celular y Medicina Regenerativa, Instituto Nacional de Rehabilitación, S.S.A., Mexico City, Mexico.
Carmen
C
Parra-Cid
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico.
Edgar
E
Rangel-López
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, S.S.A., Mexico City, Mexico. Electronic address: absada@yahoo.com.
Abel
A
Santamaría
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001058:Apomorphine; D001522:Behavior, Animal / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002219:Carbamates / Q000627:therapeutic use*; D007267:Injections; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D009048:Motor Skills / Q000187:drug effects; D017072:Neostriatum; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology; D009574:Nitro Compounds; D016627:Oxidopamine; D011422:Propionates; D051381:Rats; D017208:Rats, Wistar; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001058:Apomorphine; D001549:Benzamides; D002219:Carbamates; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D016627:Oxidopamine; D011422:Propionates; D000099252:Fatty Acid Amide Hydrolases; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C015392:3-nitropropionic acid
Endocannabinoid system; Fatty acid amide hydrolase inhibition; Mitochondrial energy depletion; Neurodegeneration; Neuromodulation; Oxidative damage; URB597