Excitotoxic damage, disrupted energy metabolism, and oxidative stress in the rat brain: antioxidant and neuroprotective effects of l-carnitine

Authors

  • Daniela Silva-Adaya,

    1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, Mexico
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    • 1

      These two authors equally contributed to this work.

  • Verónica Pérez-De La Cruz,

    1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, Mexico
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    • 1

      These two authors equally contributed to this work.

    • 2

      Programa de Doctorado en Biología Experimental, UAM.

  • María Nieves Herrera-Mundo,

    1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, Mexico
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    • 3

      Programa de Doctorado en Ciencias Biomédicas, UNAM.

  • Karina Mendoza-Macedo,

    1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, Mexico
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  • Juana Villeda-Hernández,

    1. Laboratorio de Enfermedades Neurodegenerativas, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, Mexico
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  • Zbigniew Binienda,

    1. Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas, USA
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  • Syed F. Ali,

    1. Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas, USA
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  • Abel Santamaría

    1. Laboratorio de Aminoácidos Excitadores, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, Mexico
    2. Neurochemistry Laboratory, Division of Neurotoxicology, National Center for Toxicological Research/Food and Drug Administration, Jefferson, Arkansas, USA
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Address correspondence and reprint requests to Abel Santamaría, Neurochemistry Laboratory, Division of Neurotoxicology, HFT-132, National Center for Toxicological Research/FDA, Jefferson, AR 72079, USA. E-mail: sali@nctr.fda.gov and absada@yahoo.com

Abstract

Excitotoxicity and disrupted energy metabolism are major events leading to nerve cell death in neurodegenerative disorders. These cooperative pathways share one common aspect: triggering of oxidative stress by free radical formation. In this work, we evaluated the effects of the antioxidant and energy precursor, levocarnitine (l-CAR), on the oxidative damage and the behavioral, morphological, and neurochemical alterations produced in nerve tissue by the excitotoxin and free radical precursor, quinolinic acid (2,3-pyrindin dicarboxylic acid; QUIN), and the mitochondrial toxin, 3-nitropropionic acid (3-NP). Oxidative damage was assessed by the estimation of reactive oxygen species formation, lipid peroxidation, and mitochondrial dysfunction in synaptosomal fractions. Behavioral, morphological, and neurochemical alterations were evaluated as markers of neurotoxicity in animals systemically administered with l-CAR, chronically injected with 3-NP and/or intrastriatally infused with QUIN. At micromolar concentrations, l-CAR reduced the three markers of oxidative stress stimulated by both toxins alone or in combination. l-CAR also prevented the rotation behavior evoked by QUIN and the hypokinetic pattern induced by 3-NP in rats. Morphological alterations produced by both toxins (increased striatal glial fibrillary acidic protein-immunoreactivity for QUIN and enhanced neuronal damage in different brain regions for 3-NP) were reduced by l-CAR. In addition, l-CAR prevented the synergistic action of 3-NP and QUIN to increase motor asymmetry and depleted striatal GABA levels. Our results suggest that the protective properties of l-CAR in the neurotoxic models tested are mostly mediated by its characteristics as an antioxidant agent.

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