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

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.

Sex Differences in the Behavioural Aspects of the Cuprizone-Induced Demyelination Model in Mice

“…We also know that the sex of the experimenter can affect the outcome of pain models [ 46 ]. Overall, very few studies have investigated neuropathic pain in the cuprizone-induced demyelination, with a couple showing no difference [ 28 , 45 ], and our study adding to previous work showing that neuropathic pain is associated with cuprizone administration [ 43 , 44 ].…”

“…We found that both male and female mice showed a decrease in the force needed to elicit a withdrawal response in cuprizone-treated mice ( Figure 2 A,B). In an electrical stimulation model of neuropathic pain, there was a significant decrease in the neuropathic pain threshold in C57BL/6J mice fed a 0.2% cuprizone diet [ 43 ], and female C57BL/6J mice administered cuprizone via oral gavage (400 mg/kg daily) showed a 65% reduction in the cold sensitivity reaction score measured using the acetone test [ 44 ]. In contrast, two previous studies used both mechanical and thermal stimuli in male mice administered 0.2% cuprizone, and found no differences in the withdrawal thresholds over 5 weeks [ 28 , 45 ].…”

Xanthine Oxidase Inhibitor, Febuxostat Is Effective against 5-Fluorouracil-Induced Parotid Salivary Gland Injury in Rats Via Inhibition of Oxidative Stress, Inflammation and Targeting TRPC1/CHOP Signalling Pathway

“…These current findings were supported by He et al [34], who reported that FEB attenuated ER stress-mediated renal injury in hyperuricemic nephropathy in rats. On the other hand, FEB at high concentrations had agonistic activity on TRPA1 calcium channels [35].…”

Exploring the Role of Neurotransmitters in Multiple Sclerosis: An Expanded Review

“…103 In addition, venlafaxine (60 mg•kg −1 ), another serotonin-NE reuptake inhibitor, has been indicated to display an antagonistic effect on TRPA1 calcium channels during acute demyelination in cuprizone mouse models. 104 Hence, venlafaxine may provide some protection against cuprizoneinduced demyelination. The vincamine derivative vindeburnol has been shown to elevate the expression and activity of tyrosine hydroxylase (TH) in Locus coeruleus (LC) neurons, which is the main source of NE in the CNS.…”