Neuroprotective effects of alpha-tocopherol on oxidative stress in rat striatal cultures.
Oxidative stress caused by an increase in free radicals plays an important role in neuronal death. We investigated the effects of alpha-tocopherol on oxidative stress-induced cytotoxicity using primary cultures of rat striatal neurons. alpha-Tocopherol at concentrations of 1-10 microM significantly prevented cytotoxicity induced by superoxide radical (O(2(-)) donor, 1,1'-dimethyl-4,4'-bipyridium dichloride (paraquat). In contrast, alpha-tocopherol did not affect the cytotoxicity of hydrogen peroxide (H(2)O(2)), which enhances hydroxyl radical (.OH) formation by metal-catalyzed Fenton reactions. alpha-Tocopherol significantly inhibited the cytotoxicity of nitric oxide (NO) donors, S-nitrosocysteine and 3-morpholinosydnonimine (SIN-1). alpha-Tocopherol showed potent protection against cytotoxicity induced by L-buthionine-[S,R]-sulfoximine (BSO), which causes depletion of intracellular glutathione. Moreover, alpha-tocopherol afforded a moderate but significant inhibition of cytotoxicity induced by a non-specific protein kinase inhibitor, staurosporine, which is known to induce apoptosis in many types of cells including neurons. These results suggest that alpha-tocopherol protects striatal neurons by the reduction of oxidative stress, presumably by decreasing intracellular O(2)(-) levels, and at least partly by the inhibition of apoptosis.
Osakada
Fumitaka
F
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, 46-29 Yoshida-shimoadachi-cho, Kyoto Sakyo 606-8501, Japan.
Hashino
Asami
A
Kume
Toshiaki
T
Katsuki
Hiroshi
H
Kaneko
Shuji
S
Akaike
Akinori
A
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005333:Fetus; D005721:Glutamate-Cysteine Ligase / Q000037:antagonists & inhibitors; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects*; D010269:Paraquat / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D026403:S-Nitrosothiols / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D026403:S-Nitrosothiols; D019328:Buthionine Sulfoximine; C002385:linsidomine; C021315:S-nitrosocysteine; D006861:Hydrogen Peroxide; D008981:Molsidomine; D011493:Protein Kinase C; D005721:Glutamate-Cysteine Ligase; D024502:alpha-Tocopherol; D019311:Staurosporine; D003545:Cysteine; D010269:Paraquat