Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies.
Quinolinic acid (QUIN), a well known excitotoxin that produces a pharmacological model of Huntington's disease in rats and primates, has been shown to evoke degenerative events in nerve tissue via NMDA receptor (NMDAr) overactivation and oxidative stress. In this study, the antioxidant selenium (as sodium selenite) was tested against different markers of QUIN-induced neurotoxicity under both in vitro and in vivo conditions. In the in vitro experiments, a concentration-dependent effect of selenium was evaluated on the regional peroxidative action of QUIN as an index of oxidative toxicity in rat brain synaptosomes. In the in vivo experiments, selenium (0.625 mg per kg per day, i.p.) was administered to rats for 5 days, and 2 h later animals received a single unilateral striatal injection of QUIN (240 nmol/ micro L). Rats were killed 2 h after the induction of lesions with QUIN to measure lipid peroxidation and glutathione peroxidase (GPx) activity in striatal tissue. In other groups, the rotation behavior, GABA content, morphologic alterations, and the corresponding ratio of neuronal damage were all evaluated as additional markers of QUIN-induced striatal toxicity 7 days after the intrastriatal injection of QUIN. Selenium decreased the peroxidative action of QUIN in synaptosomes both from whole rat brain and from the striatum and hippocampus, but not in the cortex. A protective concentration-dependent effect of selenium was observed in QUIN-exposed synaptosomes from whole brain and hippocampus. Selenium pre-treatment decreased the in vivo lipid peroxidation and increased the GPx activity in QUIN-treated rats. Selenium also significantly attenuated the QUIN-induced circling behavior, the striatal GABA depletion, the ratio of neuronal damage, and partially prevented the morphologic alterations in rats. These data suggest that major features of QUIN-induced neurotoxicity are partially mediated by free radical formation and oxidative stress, and that selenium partially protects against QUIN toxicity.
Santamaría
Abel
A
Departamento de Neuroquímica and Neuromorfología Celular, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Mexico City, Mexico.
Salvatierra-Sánchez
Raquel
R
Vázquez-Román
Beatriz
B
Santiago-López
Dario
D
Villeda-Hernández
Juana
J
Galván-Arzate
Sonia
S
Jiménez-Capdeville
María E
ME
Ali
Syed F
SF
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001923:Brain Chemistry; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy*; D017378:Quinolinic Acid; D051381:Rats; D017208:Rats, Wistar; D012643:Selenium / Q000627:therapeutic use*; D018038:Sodium Selenite / Q000627:therapeutic use; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000975:Antioxidants; D018696:Neuroprotective Agents; D005680:gamma-Aminobutyric Acid; D017378:Quinolinic Acid; D012643:Selenium; D018038:Sodium Selenite