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ToxSci Advance Access originally published online on April 15, 2003
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Toxicological Sciences 73, 416-422 (2003)
Copyright © 2003 by the 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 and Parayanthala V. Mohanan{dagger}

* The University of Tsukuba, Institute of Community Medicine, Tsukuba, Ibaraki, 305-8575 Japan; and {dagger} Recipient of a Research Fellowship for Foreign Scientists on the Japan Society for the Promotion of Science

The effects of L-cysteine on mitochondrial DNA (mtDNA) in mouse brain were investigated both in vivoandin 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) preinjection of melatonin (20 mg/kg) or an intracerebroventricular preinjection of ganglioside GT1b (90 nmol/animal). Furthermore, in in vitroexperiments, 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 cotreatment 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.

Key Words: melatonin; ganglioside GT1b; L-cysteine; mitochondrial DNA; lipid peroxidation; seizures; hydroxyl radical.


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