Neuroprotective Effect of Apolipoprotein D in Cuprizone-Induced Cell Line Models: A Potential Therapeutic Approach for Multiple Sclerosis and Demyelinating Diseases.

Eva Martínez-Pinilla,Ignacio M Larráyoz,Núria Rubio-Sardón,Jorge Tolivia,Rafael Peláez,Enrique García-Álvarez,Ana Navarro,Eva Del Valle

doi:10.3390/ijms22031260

Abstract

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.

Highlights

Apolipoprotein D (Apo D) is a well-known lipocalin family member that plays a key role in the transport, metabolism and homeostasis of some lipids due to its ability to bind cholesterol, arachidonic acid, steroids, retinoic acid or anandamide, among other small hydrophobic ligands [1,2,3]
Our results showed that the changes induced by CPZ in Apo D expression are minimal despite the dose and time-dependent cytotoxic damage previously reported for CPZ in the same conditions
Various authors, including us, have used in vitro assays to demonstrate that H2O2, amyloid beta-peptide, lipopolysaccharide, paraquat as well as other acute short-term oxidative stressors induce a time- and dosedependent effect on Apo D expression [55,56,57,58,59]

Summary

Introduction

Apolipoprotein D (Apo D) is a well-known lipocalin family member that plays a key role in the transport, metabolism and homeostasis of some lipids due to its ability to bind cholesterol, arachidonic acid, steroids, retinoic acid or anandamide, among other small hydrophobic ligands [1,2,3]. Apo D shows various exposed hydrophobic residues located in three of its extended loops which may contribute to Apo D association with lipids and seem to explain its potential as multiligand and multifunctional protein [4,5]. Most importantly, they have been linked to the ability of Apo D to bind and reduce oxidized lipids, and thereby inhibit radical-propagation of lipid hydroperoxides [6,7,8]. The potential neuroprotective and prosurvival roles for Apo D have been proven in animal models where the overexpression of this protein confers greater protection against oxidative stress and contributes significantly to the regulation of longevity; the experimental lack of Apo D causes opposite results [11,12]

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