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.