Copper blocks quinolinic acid neurotoxicity in rats: contribution of antioxidant systems.
Reactive oxygen species and oxidative stress are involved in quinolinic acid (QUIN)-induced neurotoxicity. QUIN, a N-methyl-D-aspartate receptor (NMDAr) agonist and prooxidant molecule, produces NMDAr overactivation, excitotoxic events, and direct reactive oxygen species formation. Copper is an essential metal exhibiting both modulatory effects on neuronal excitatory activity and antioxidant properties. To investigate whether this metal is able to counteract the neurotoxic and oxidative actions of QUIN, we administered copper (as CuSO(4)) intraperitoneally to rats (2.5, 5.0, 7.5, and 10.0 mg/kg) 30 min before the striatal infusion of 1 microliter of QUIN (240 nmol). A 5.0 mg/kg CuSO(4) dose significantly increased the copper content in the striatum, reduced the neurotoxicity measured both as circling behavior and striatal gamma-aminobutyric acid (GABA) depletion, and blocked the oxidative injury evaluated as striatal lipid peroxidation (LP). In addition, copper reduced the QUIN-induced decreased striatal activity of Cu,Zn-dependent superoxide dismutase, and increased the ferroxidase activity of ceruloplasmin in cerebrospinal fluid from QUIN-treated rats. However, copper also produced significant increases of plasma lactate dehydrogenase activity and mortality at the highest doses employed (7.5 and 10.0 mg/kg). These results show that at low doses, copper exerts a protective effect on in vivo QUIN neurotoxicity.
Santamaría
Abel
A
Laboratorio de Aminoácidos Excitadores/Departamento de Neuroquímica, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, México, D.F., Mexico.
Flores-Escartín
Abigail
A
Martínez
Juan Carlos
JC
Osorio
Laura
L
Galván-Arzate
Sonia
S
Pedraza-Chaverrí
José
J
Chaverrí
José Pedraza
JP
Maldonado
Perla D
PD
Medina-Campos
Omar N
ON
Jiménez-Capdeville
María E
ME
Manjarrez
Joaquín
J
Ríos
Camilo
C
D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology*; D015153:Blotting, Western; D001835:Body Weight; D002570:Ceruloplasmin / Q000378:metabolism; D003300:Copper / Q000378:metabolism*; D019327:Copper Sulfate / Q000378:metabolism; D005609:Free Radicals; D007477:Ions; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D018384:Oxidative Stress; D017378:Quinolinic Acid / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists; D013482:Superoxide Dismutase / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D000975:Antioxidants; D005609:Free Radicals; D007477:Ions; D017382:Reactive Oxygen Species; D016194:Receptors, N-Methyl-D-Aspartate; D005680:gamma-Aminobutyric Acid; D003300:Copper; D007770:L-Lactate Dehydrogenase; D013482:Superoxide Dismutase; D002570:Ceruloplasmin; D017378:Quinolinic Acid; D019327:Copper Sulfate