Synthesis and Evaluation of the Effects of Nanoparticles of Atorvastatin and Atorvastatin on Cuprizone-Induced Demyelination: Modulation of the Nrf2/NF-kB Signaling Pathway.

Abstract

Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by damage to the myelin sheath and, over time, by progressive neurological disability. Statins have attracted attention in MS research owing to their anti-inflammatory and neuroprotective effects.

Objectives: This study assessed whether atorvastatin could ameliorate cuprizone-induced behavioral and histopathological changes in the brains of male C57BL/6 mice.

Methods: All groups of mice, except the control group, which received a normal diet, were fed 0.2% cuprizone (CPZ) in their daily diet for 6 weeks to induce demyelination. The treatment groups received atorvastatin (1, 2, or 4 mg/kg/day, i.p.) or nano-atorvastatin (2 mg/kg/day, i.p.) during the final 2 weeks of the study. At the end of the study, behavioral tests were conducted, and immunofluorescence assessment of NF-kB p65 and Nrf2 in the corpus callosum was conducted.

Results: CPZ caused progressive weight loss by the end of the study compared with the control group; this effect was reversed by treatment with atorvastatin and nano-atorvastatin. All behavioral tests showed reduced motor coordination in the CPZ group (P < 0.001) compared with the control group. Administration of atorvastatin and nano-atorvastatin during the last 2 weeks reversed these motor deficits. Histopathological examination showed significant demyelination in the CPZ group, which was reversed by atorvastatin injections. Furthermore, CPZ significantly decreased Nrf2 levels (P < 0.001) and increased NF-kB p65 levels (P < 0.001) in the corpus callosum; these changes were stabilized in the atorvastatin and nano-atorvastatin groups.

Conclusions: Atorvastatin may attenuate CPZ-induced toxicity by reducing demyelination and modulating the NF-kB p65 and Nrf2 signaling pathways.