In vivo and in vitro effects of melatonin or ganglioside GT1B on L-cysteine-induced brain mitochondrial DNA damage in mice.
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 micromol/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 degrees 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 microM), 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.
Yamamoto
Hiro-aki
HA
The University of Tsukuba, Institute of Community Medicine, Tsukuba, Ibaraki, 305-8575 Japan. hiro_aki@d4.dion.ne.jp
Mohanan
Parayanthala V
PV
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003545:Cysteine / Q000008:administration & dosage / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects*; D004272:DNA, Mitochondrial / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D005732:Gangliosides / Q000494:pharmacology*; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D015227:Lipid Peroxidation; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D051379:Mice; D008815:Mice, Inbred Strains; D017382:Reactive Oxygen Species / Q000378:metabolism; D014020:Tissue Extracts / Q000378:metabolism
D004272:DNA, Mitochondrial; D005732:Gangliosides; D017382:Reactive Oxygen Species; D014020:Tissue Extracts; D017665:Hydroxyl Radical; C016481:trisialoganglioside GT1; D008550:Melatonin; D003545:Cysteine