Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress.

Dragos Paul Mihai,Cristina Elena Zbarcea,Cosmin I Ciotu,Oana Cristina Seremet,Simona Negres,Anca Zanfirescu,Corina Andrei,Michael J M Fischer,Anca Ungurianu,Octavian Tudorel Olaru,George Mihai Nitulescu,Cornel Chirita

doi:10.3390/ijms22137183

Abstract

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

Highlights

Multiple sclerosis (MS) is a chronic, debilitating autoimmune disorder of the central nervous system (CNS) which occurs in a significant number of young adults worldwide, affecting 30 per 100,000 persons according to WHO [1,2]
Locomotor activity following the 5-week cuprizone (CPZ) and drug treatments was investigated, and baseline measurements served as a covariate
Risperidone and febuxostat for five weeks reduced the effects of cuprizone-induced demyelination in mice, but only risperidone yielded significant results after histological analysis

Summary

Introduction

Multiple sclerosis (MS) is a chronic, debilitating autoimmune disorder of the central nervous system (CNS) which occurs in a significant number of young adults worldwide, affecting 30 per 100,000 persons according to WHO [1,2]. Current therapeutic strategies for MS include immunomodulatory molecules (i.e., glatiramer acetate, dimethyl fumarate, fingolimod, mitoxantrone) and monoclonal antibodies for relapsing-remitting forms (natalizumab, ocrelizumab, alemtuzumab) [6,7,8,9,10,11]. These approved small molecules and biologic therapies have limited efficacy, high costs and an unfavorable safety profile, the need for discovering novel therapeutic agents active in MS [7,12].

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