Protective effects of 1α,25-(OH)2D3 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 dopaminergic neurons against the neurotoxic effects of glutamate and dopaminergic toxins using rat mesecephalic culture. Brief glutamate exposure elicited cytotoxicity in both dopaminergic and non-dopaminergic neurons. Pretreatment, but not co-administration, of 1 alpha ,25-(OH)(2)D-3 protected both types of neurons against the cytotoxicity of glutamate in a concentration- and time-dependent manner. The neuroprotective effect of 1 alpha ,25-(OH)(2)D-3 was inhibited by the protein synthesis inhibitor, cycloheximide. To investigate the mechanisms of these neuroprotective effects, we examined the effects of 1 alpha .25-(OH)(2)D-3 on neurotoxicity induced by calcium ionophore and reactive oxygen species (ROS). Pretreatment with 1 alpha ,25-(OH)(2)D-3 protected both types of neurons against the cytotoxicity induced by A23187 in a concentration-dependent manner. Furthermore, 24-h pretreatment with 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-hydroxydopamine (6-OHDA) exerted selective neurotoxicity on dopaminergic neurons, 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 dopaminergic neurons against cytotoxicity induced by glutamate and dopaminergic toxins by facilitating cellular functions that reduce oxidative stress. (C) 2001 Elsevier Science Ltd. All rights reserved.