Apolipoprotein D (
Apo D) overexpression is a general finding across neurodegenerative conditions so the role of this
apolipoprotein in various neuropathologies such as
multiple sclerosis (MS) has aroused a great interest in last years. However, its mode of action, as a promising compound for the development of
neuroprotective drugs, is unknown. The aim of this work was to address the potential of
Apo D to prevent the action of
cuprizone (CPZ), a toxin widely used for developing MS models, in oligodendroglial and
neuroblastoma cell lines. On one hand, immunocytochemical quantifications and gene expression measures showed that CPZ compromised neural mitochondrial metabolism but did not induce the expression of
Apo D, except in extremely high doses in neurons. On the other hand, assays of neuroprotection demonstrated that
antipsychotic drug,
clozapine, induced an increase in
Apo D synthesis only in the presence of CPZ, at the same time that prevented the loss of viability caused by the toxin. The effect of the exogenous addition of human
Apo D, once internalized, was also able to directly revert the loss of cell viability caused by treatment with CPZ by a
reactive oxygen species (ROS)-independent mechanism of action. Taken together, our results suggest that increasing
Apo D levels, in an endo- or exogenous way, moderately prevents the neurotoxic effect of CPZ in a cell model that seems to replicate some features of MS which would open new avenues in the development of interventions to afford MS-related neuroprotection.