Chronic Sulfasalazine Treatment in Mice Induces System xc - - Independent Adverse Effects.

Lise Verbruggen,Eduard Bentea,Olaya Lara,Azzedine Gharib,Lauren Deneyer,Pauline Janssen,Lindsay Sprimont,Charles Nicaise,Hideyo Sato,Ann Massie,Laura De Pauw

doi:10.3389/fphar.2021.625699

Lise Verbruggen, Eduard Bentea + Show 9 more

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https://doi.org/10.3389/fphar.2021.625699

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Abstract

Despite ample evidence for the therapeutic potential of inhibition of the cystine/glutamate antiporter system xc − in neurological disorders and in cancer, none of the proposed inhibitors is selective. In this context, a lot of research has been performed using the EMA- and FDA-approved drug sulfasalazine (SAS). Even though this molecule is already on the market for decades as an anti-inflammatory drug, serious side effects due to its use have been reported. Whereas for the treatment of the main indications, SAS needs to be cleaved in the intestine into the anti-inflammatory compound mesalazine, it needs to reach the systemic circulation in its intact form to allow inhibition of system xc −. The higher plasma levels of intact SAS (or its metabolites) might induce adverse effects, independent of its action on system xc −. Some of these effects have however been attributed to system xc − inhibition, calling into question the safety of targeting system xc −. In this study we chronically treated system xc − - deficient mice and their wildtype littermates with two different doses of SAS (160 mg/kg twice daily or 320 mg/kg once daily, i.p.) and studied some of the adverse effects that were previously reported. SAS had a negative impact on the survival rate, the body weight, the thermoregulation and/or stress reaction of mice of both genotypes, and thus independent of its inhibitory action on system xc −. While SAS decreased the total distance travelled in the open-field test the first time the mice encountered the test, it did not influence this parameter on the long-term and it did not induce other behavioral changes such as anxiety- or depressive-like behavior. Finally, no major histological abnormalities were observed in the spinal cord. To conclude, we were unable to identify any undesirable system xc −-dependent effect of chronic administration of SAS.

Highlights

System xc− is a cystine/glutamate antiporter with xCT (Slc7a11) as specific subunit and is located mainly in the central nervous system and peripheral organs related to the immune system. xCT expression is enhanced in conditions of increased oxidative stress and/or inflammation, and inhibition of system xc− has been proposed as a treatment strategy for several neurological disorders as well as for diverse cancer types (Lewerenz et al., 2013; Massie et al, 2015; Koppula et al, 2018; Liu et al, 2020).despite many attempts, till none of the available inhibitors are selectively targeting system xc−
Given inconsistent reports on the use of SAS in disorders characterized by deficits in the spinal cord such as multiple sclerosis (MS), we further focused on the involvement of system xc− in possible toxic effects of chronic SAS treatment on the spinal cord
Injections with both saline and 160 mg/kg of SAS induced the same degree of weight loss in xCT+/+ mice, which was stable over the four weeks of treatment (Figure 2C; Sidak’s multiple comparisons test (MCT): p 0.9251), whereas the weight loss was more pronounced in xCT+/+ mice treated with

Summary

Introduction

System xc− is a cystine/glutamate antiporter with xCT (Slc7a11) as specific subunit and is located mainly in the central nervous system and peripheral organs related to the immune system. xCT expression is enhanced in conditions of increased oxidative stress and/or inflammation, and inhibition of system xc− has been proposed as a treatment strategy for several neurological disorders as well as for diverse cancer types (Lewerenz et al., 2013; Massie et al, 2015; Koppula et al, 2018; Liu et al, 2020).despite many attempts, till none of the available inhibitors are selectively targeting system xc−. Using xCT−/− mice, we demonstrated that system xc− is the major source of extracellular glutamate in different brain regions (De Bundel et al, 2011; Massie et al, 2011). This glutamate can modulate the glutamatergic neurotransmission but when extracellular glutamate concentrations rise, e.g. in case of injury or neurological disorders (Mehta et al, 2013; Olloquequi et al., 2018), this glutamate can lower the threshold for glutamate toxicity (excitotoxicity) and thereby induce or further promote disease progression. XCT−/− mice have been shown to be protected in models for several neurological disorders

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