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ToxSci Advance Access published online on April 15, 2003
Toxicological Sciences, doi:10.1093/toxsci/kfg089
Toxicological Sciences © Society of Toxicology 2003; all rights reserved
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Received January 16, 2003; accepted March 17, 2003
© 2003 Society of Toxicology

Neurotoxicology

In Vivo and in Vitro Effects of Melatonin or Ganglioside GT1b on L-Cysteine-Induced Brain Mitochondrial DNA Damage in Mice

Hiro-aki Yamamoto 1* Parayanthala V. Mohanan 1

1 The University of Tsukuba, Institute of Community Medicine, Tsukuba, Ibaraki, 305-8575 Japan

* To whom correspondence should be addressed. E-mail: hiro_aki{at}d4.dion.ne.jp.


  Abstract

The effects of L-cysteine on mitochondrial DNA (mtDNA) in mouse brain were investigated both in vivo and in vitro. An intracerebroventricular (icv) injection of L-cysteine (1.25 µmol/animal) caused mtDNA damage in brain frontal and central portions of the cortex, broad-spectrum limbic and severe sustained seizures in mice, and increased lipid peroxidation in the whole brain. The L-cysteine-mediated effects were prevented by an intraperitoneal (ip) pre-injection of melatonin (20 mg/kg) or an intracerebroventricular pre-injection of ganglioside GT1b (90 nmol/animal).

Furthermore, in vitro experiments, L-cysteine (0.05, 0.5 or 1.0 mM) caused damage to brain mtDNA and increased lipid peroxidation in a concentration-dependent manner. When Incubated at 37°C for 20 or 60 min with a homogenate prepared from whole mouse brains. However, the mtDNA damage and the increased lipid peroxidation were completely abolished by a co-treatment with melatonin (1.5 mM), a potent scavenger of the hydroxyl radical (·OH) or ganglioside GT1b (60 µM), a potent inhibitor of glutamate receptor mediated activation and translocation of protein kinase C and lipid peroxidation. These results suggest that reactive oxygen species including the ·OH may be involved in L-cysteine-induced brain mtDNA damage, lipid peroxidation and development of seizures in mice. Therefore, we concluded that ·OH scavengers such as the pineal hormone melatonin and ganglioside GT1b can protect against brain mtDNA damage, seizures and lipid peroxidation induced by reactive oxygen species producers, such as L-cysteine.

Melatonin, ganglioside GT1b, L-cysteine, mitochondrial DNA, lipid peroxidation, seizures, hydroxyl radical .


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