Protective effects of 1 alpha,25-(OH)(2)D-3 against the neurotoxicity of glutamate and reactive oxygen species in mesencephalic culture

This study was undertaken to determine whether 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25-(OH)(2)D-3], an active metabolite of vitamin D, protects dop aminergic neurons against the neurotoxic effects of glutamate and dopaminer gic toxins using rat mesecephalic culture. Brief glutamate exposure elicite d cytotoxicity in both dopaminergic and non-dopaminergic neurons. Pretreatm ent, but not co-administration, of 1 alpha ,25-(OH)(2)D-3 protected both ty pes of neurons against the cytotoxicity of glutamate in a concentration- an d time-dependent manner. The neuroprotective effect of 1 alpha ,25-(OH)(2)D -3 was inhibited by the protein synthesis inhibitor, cycloheximide. To inve stigate the mechanisms of these neuroprotective effects, we examined the ef fects of 1 alpha .25-(OH)(2)D-3 on neurotoxicity induced by calcium ionopho re and reactive oxygen species (ROS). Pretreatment with 1 alpha ,25-(OH)(2) D-3 protected both types of neurons against the cytotoxicity induced by A23 187 in a concentration-dependent manner. Furthermore, 24-h pretreatment wit h 1 alpha .25-(OH)(2)D-3 concentration-dependently protected both types of neurons from ROS-induced cytotoxicity. A 24-h incubation with 1 alpha ,25-( OH)(2)D-3 inhibited the increase in intracellular ROS level following H2O2 exposure. A 24-h exposure to 1-methyl-4-phenylpyridium ion (MPP+) or 6-hydr oxydopamine (6-OHDA) exerted selective neurotoxicity on dopaminergic neuron s, and these neurotoxic effects were ameliorated by 1 alpha -25-(OH)(2)D-3. These results suggest that 1 alpha ,25-(OH)(2)D-3 provides protection of d opaminergic neurons against cytotoxicity induced by glutamate and dopaminer gic toxins by facilitating cellular functions that reduce oxidative stress. (C) 2001 Elsevier Science Ltd. All rights reserved.