Abstract
BackgroundLaquinimod is an immunomodulatory drug under clinical investigation for the treatment of the progressive form of multiple sclerosis (MS) with both anti-inflammatory and neuroprotective effects. Excitotoxicity, a prominent pathophysiological feature of MS and of its animal model, experimental autoimmune encephalomyelitis (EAE), involves glutamate transporter (GluT) dysfunction in glial cells.The aim of this study was to assess whether laquinimod might exert direct neuroprotective effects by interfering with the mechanisms of excitotoxicity linked to GluT function impairments in EAE.MethodsOsmotic minipumps allowing continuous intracerebroventricular (icv) infusion of laquinimod for 4 weeks were implanted into C57BL/6 mice before EAE induction. EAE cerebella were taken to perform western blot and qPCR experiments. For ex vivo experiments, EAE cerebellar slices were incubated with laquinimod before performing electrophysiology, western blot, and qPCR.ResultsIn vivo treatment with laquinimod attenuated EAE clinical score at the peak of the disease, without remarkable effects on inflammatory markers. In vitro application of laquinimod to EAE cerebellar slices prevented EAE-linked glutamatergic alterations without mitigating astrogliosis and inflammation. Moreover, such treatment induced an increase of Slcla3 mRNA coding for the glial glutamate–aspartate transporter (GLAST) without affecting the protein content. Concomitantly, laquinimod significantly increased the levels of the glial glutamate transporter 1 (GLT-1) protein and pharmacological blockade of GLT-1 function fully abolished laquinimod anti-excitotoxic effect.ConclusionsOverall, our results suggest that laquinimod protects against glutamate excitotoxicity of the cerebellum of EAE mice by bursting the expression of glial glutamate transporters, independently of its anti-inflammatory effects.
Highlights
Laquinimod is an immunomodulatory drug under clinical investigation for the treatment of the progressive form of multiple sclerosis (MS) with both anti-inflammatory and neuroprotective effects
By performing ex vivo and in vivo studies in EAE mice, we investigated the direct effect of laquinimod on cerebellar glutamatergic excitotoxicity to elucidate the molecular mechanisms responsible for its neuroprotective effects
Rise time values were unchanged among groups (Fig. 6c; rise time: EAE-vhl 1.416 ± 0.062 ms; EAE-laquinimod 1.362 ± 0.077 ms; EAE-laquinimodDHK 1.57 ± 0.107 ms). These results indicate that laquinimod acute treatment ameliorates glutamatergic transmission in EAE cerebellum by inducing glutamate transporter 1 (GLT-1) expression and improving its function
Summary
Laquinimod is an immunomodulatory drug under clinical investigation for the treatment of the progressive form of multiple sclerosis (MS) with both anti-inflammatory and neuroprotective effects. Approved therapies for MS are based on immunomodulatory or immunosuppressive Both clinical [5,6,7] and experimental studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), highlighted anti-inflammatory and neuroprotective effects of laquinimod, a once daily immunomodulatory agent under clinical investigation for the progressive form of MS [8,9,10,11,12,13,14,15,16]. Laquinimod reduced the number of active lesions [17, 18] and prevented the reduction in brain volume in MS patients [5]. It has been demonstrated that the aryl hydrocarbon receptor (AhR) is a molecular target of laquinimod in the EAE model [9]
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