Effect of 1,25-dihydroxyvitamin D-3 on cultured mesencephalic dopaminergicneurons to the combined toxicity caused by L-buthionine sulfoximine and 1-methyl-4-phenylpyridine

A decrease in intracellular glutathione content may be related to the prima ry event in Parkinson's disease, so increasing the glutathione level may ha ve a therapeutic benefit. The biologically active form of vitamin D, 1,25-d ihydroxyvitamin D-3 [1,25-(OH)(2)D-3] has been recently reported to enhance the intracellular glutathione concentration in the central nervous system. Exposing rat cultured mesencephalic neurons for 24 hr to a mixture of L-bu thionine sulfoximine (BSO) and 1-methyl-4-phenylpyridium ions (MPP+) result ed in a relatively selective damage to dopaminergic neurons. This damage ha s been accompanied by a reduction of intracellular glutathione levels. Low doses, i.e., 1-100 nM, of 1,25-(OH)(2)D-3 protect cultured dopaminergic neu rons against this toxicity, although higher concentrations of this active f orm of vitamin D have been found to enhance the toxic effect. Generation of reactive oxygen species (ROS) by this toxicity has been attenuated in cult ures being pretreated with low concentrations of 1,25-(OH)(2)D-3. Because t he hormone increases the intracellular glutathione content in cultures, det ermining how this hormone suppresses ROS generation may involve the enhance ment of the antioxidative system. These data suggest that low doses of 1,25 -(OH)(2)D-3 are able to protect mesencephalic dopaminergic neurons against BSO/MPP+-induced toxicity that causes a depletion in glutathione content. J . Neurosci. Res. 62:374-382, 2000. (C) 2000 Wiley-Liss, Inc.