Melatonin maintains glutathione homeostasis in kainic acid-exposed rat brain tissues.
Reduced glutathione (GSH) is a key component of the cellular defense cascade against injury caused by reactive oxygen species. Because kainic acid (KA) neurotoxicity is probably mediated at least in part by oxidative stress, we examined the influence of KA treatment on GSH content and GSH-related enzyme activities in adult rats. A single injection of KA (10 mg/kg i.p.) time-dependently decreased forebrain GSH (maximal reduction at 48 h). KA also markedly lowered GSH levels in amygdala and hippocampus, but not in the corpus striatum, which is resistant to KA injury. The pineal secretory product melatonin has been shown to exert neuroprotective effects against KA-induced excitotoxicity in rats. Melatonin (2.5 mg/kg i.p., administered four times) partially prevented all decreases in GSH of KA-treated rats. These neuroprotective effects of melatonin may result from a sparing of glutathione reductase, which decreased in KA-treated but not in KA/melatonin-treated animals. Moreover, KA caused a rapid decrease in the GSH content of cultured cerebellar granule neurons but not astrocytes. These cell types both express functional KA receptors, but only the former are sensitive to reactive oxygen species-dependent KA injury. Melatonin counteracted the changes in GSH induced by KA in cultured cerebellar granule neurons. Our results suggest that melatonin prevents the neurotoxic effects of reactive oxygen species linked to KA receptor activation by maintaining cellular GSH homeostasis.
Floreani
M
M
Department of Pharmacology, University of Padua, Italy.
Skaper
S D
SD
Facci
L
L
Lipartiti
M
M
Giusti
P
P
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D007700:Kinetics; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D014018:Tissue Distribution
D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D005978:Glutathione; D008550:Melatonin; D007608:Kainic Acid; D019803:Glutathione Disulfide