Neuroprotective effect of WIN55,212-2 against 3-nitropropionic acid-induced toxicity in the rat brain: involvement of CB1 and NMDA receptors.
The endocannabinoid system (ECS), and agonists acting on cannabinoid receptors (CBr), are known to regulate several physiological events in the brain, including modulatory actions on excitatory events probably through N-methyl-D-aspartate receptor (NMDAr) activity. Actually, CBr agonists can be neuroprotective. The synthetic CBr agonist WIN55,212-2 acts mainly on CB1 receptor. In turn, the mitochondrial toxin 3-nitropropionic acid (3-NP) produces striatal alterations in rats similar to those observed in the brain of Huntington's disease patients. Herein, the effects of WIN55,212-2 were tested on different endpoints of the 3-NP-induced toxicity in rat brain synaptosomes and striatal tissue. Motor activity was also evaluated. The 3-NP (1 mM)-induced mitochondrial dysfunction and lipid peroxidation was attenuated by WIN55,212-2 (1 µM) in synaptosomal fractions. The intrastriatal bilateral injection of 3-NP (500 nmol/µL) to rats increased lipid peroxidation and locomotor activity, augmented the rate of cell damage, and decreased the striatal density of neuronal cells. These alterations were accompanied by transcriptional changes in the NMDA (NR1 subunit) content. The administration of WIN55212-2 (1 mg/kg, i.p.) to rats for six consecutive days, before the 3-NP injection, exerted preventive effects on all alterations elicited by the toxin. The prevention of the 3-NP-induced NR1 transcriptional alterations by the CBr agonist together with the increase of CB1 content suggest an early reduction of the excitotoxic process via CBr activation. Our results demonstrate a protective role of WIN55,212-2 on the 3-NP-induced striatal neurotoxicity that could be partially related to the ECS stimulation and induction of NMDAr hypofunction, representing an effective therapeutic strategy at the experimental level for further studies.
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSAMexico City 14269, Mexico; Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-IztapalapaMexico City 09310, Mexico.
Marisol
M
Maya-López
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Ana Laura
AL
Colín-González
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Gabriela
G
Aguilera
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
María Eduarda
ME
de Lima
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Ana
A
Colpo-Ceolin
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Edgar
E
Rangel-López
Laboratorio de Patología Experimental, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Juana
J
Villeda-Hernández
Laboratorio de Neuropatología, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Daniel
D
Rembao-Bojórquez
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Córdoba Cordoba, Spain.
Isaac
I
Túnez
Departamento de Investigación Básica, Instituto Nacional de Geriatría, SSA Mexico City 10200, Mexico.
Armando
A
Luna-López
Departamento de Biología de la Reproducción, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa Mexico City 09310, Mexico.
Roberto
R
Lazzarini-Lechuga
Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa Mexico City 09310, Mexico.
Viridiana Yazmín
VY
González-Puertos
Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa Mexico City 09310, Mexico.
Pedro
P
Posadas-Rodríguez
Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa Mexico City 09310, Mexico.
Alejandro
A
Silva-Palacios
Departamento de Ciencias de la Salud, División de Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana-Iztapalapa Mexico City 09310, Mexico.
Mina
M
Königsberg
Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía, SSA Mexico City 14269, Mexico.
Abel
A
Santamaría
212-2; 3-Nitropropionic acid; WIN55; cannabinoid receptor agonists; endocannabinoid system; mitochondrial energy depletion; neuroprotection