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Laquinimod Ameliorates Excitotoxic Damage by Regulating Glutamate Re

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Laquinimod Ameliorates Excitotoxic Damage by Regulating Glutamate Re Gentile et al. Journal of Neuroinflammation (2018) 15:5 DOI 10.1186/s12974-017-1048-6 RESEARCH Open Access Laquinimod ameliorates excitotoxic damage by regulating glutamate re-uptake Antonietta Gentile1,2†, Alessandra Musella3,4†, Francesca De Vito1,2,4, Diego Fresegna1,2,4, Silvia Bullitta1,2, Francesca Romana Rizzo1,2, Diego Centonze1,2* and Georgia Mandolesi3,4 Abstract Background: 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. 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. Methods: Osmotic 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. Results: In 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. Conclusions: Overall, 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. Keywords: Excitotoxicity, Glutamate transporters, Experimental autoimmune encephalomyelitis, Cerebellum, Spontaneous excitatory post-synaptic currents, Neuroprotection Background drugs, although effective therapies are expected to interact Multiple sclerosis (MS) is a chronic immune-mediated directly with the CNS and prevent deterioration, reverse disease of the central nervous system (CNS) characterized injury, and restore function to counteract not only by demyelination and neurodegeneration. Nowadays, demyelination but also both axonal damage and synapto- neurodegeneration is not only viewed as the culminating pathy [2–4]. event of demyelination but is likely supposed to develop Both clinical [5–7] and experimental studies in the in parallel [1]. Currently approved therapies for MS are mouse model of MS, experimental autoimmune enceph- based on immunomodulatory or immunosuppressive alomyelitis (EAE), highlighted anti-inflammatory and neuroprotective effects of laquinimod, a once daily im- * Correspondence: [email protected] munomodulatory agent under clinical investigation for †Equal contributors the progressive form of MS [8–16]. Laquinimod reduced 1Unit of Neurology and Unit of Neurorehabilitation, IRCCS Istituto the number of active lesions [17, 18] and prevented the Neurologico Mediterraneo (INM) Neuromed, 86077 Pozzilli, IS, Italy 2Department of Systems Medicine, Multiple Sclerosis Research Center, Tor reduction in brain volume in MS patients [5]. Further- Vergata University, Via Montpellier, 1, 00133 Rome, Italy more, laquinimod increased levels of brain-derived Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Gentile et al. Journal of Neuroinflammation (2018) 15:5 Page 2 of 13 neurotrophic factor (BDNF) in the serum of MS patients of MOG35–55 emulsion to induce EAE by active [15] and in the CNS of EAE mice in association with a immunization. The emulsion was prepared under sterile reduced CNS injury [8]. Interestingly, laquinimod, which conditions using MOG35–55 (85% purity; Espikem) in can cross the blood–brain barrier [19], was reported to 300 μl of complete Freund’s adjuvant (CFA; Difco) con- influence the viability of neurons and oligodendrocytes taining Mycobacterium tuberculosis (8 mg/ml, strain independently of its anti-inflammatory effects. Consist- H37Ra; Difco) and emulsified with phosphate buffer so- ently, laquinimod reduced demyelination, axonal lution (PBS). All animals were injected with 500 ng of damage, and lesion size in EAE [8, 20] and compensated pertussis toxin (Sigma) intravenously on the day of for the altered glutamatergic and GABAergic transmission immunization and 2 days later. Control animals received in the EAE striatum [14]. Recently, it has been demon- the same treatment as EAE mice without the immuno- strated that the aryl hydrocarbon receptor (AhR) is a gen MOG peptide, including complete CFA and pertus- molecular target of laquinimod in the EAE model [9]. sis toxin (referred to hereafter as “CFA”). Animals were The mechanisms by which laquinimod exerts its effects daily scored for clinical symptoms of EAE according to are likely different and not yet fully elucidated. In particu- the following scale: 0 = no clinical signs, 1 = flaccid tail, lar, little is known about its direct activity on excitotoxic 2 = hindlimb weakness, 3 = hindlimb paresis, 4 = damage. In MS and EAE, excitotoxicity, which involves complete bilateral hindlimb paralysis, and 5 = death due glutamate transporter (GluT) dysfunction, is an important to EAE; intermediate clinical signs were scored by add- link between neuroinflammation and neurodegeneration ing 0.5. For each animal, the onset day was recorded as [1, 21–24]. In this regard, we recently provided evidence the day post-immunization (dpi) when it showed the of a defective glutamate uptake and excitotoxic damage in first clinical manifestations. the EAE cerebellum [25], highlighting a dysfunction of the glial glutamate–aspartate transporter (GLAST; excitatory Laquinimod formulation for minipump and surgery (in amino acid transporter EAAT 1 in humans) at the level of vivo experiments) the Purkinje cell tripartite synapse. GLAST dysfunction is Laquinimod (Teva Pharmaceutical Industries, Netanya, caused by a post-transcriptional downregulation mediated Israel) was dissolved in 0.9% NaCl. One week before by miR-142-3-p [26]. immunization, mice were implanted with subcutaneous Based on these observations, by performing ex vivo osmotic minipumps allowing continuous intracerebro- and in vivo studies in EAE mice, we investigated the dir- ventricular (icv) infusion of either vehicle (vhl) or ect effect of laquinimod on cerebellar glutamatergic laquinimod (1.25 mg/kg/day) for 4 weeks [25, 27]. excitotoxicity to elucidate the molecular mechanisms re- sponsible for its neuroprotective effects. Electrophysiology Mice were killed by cervical dislocation, and cerebellar Methods parasagittal slices (210 μm) were prepared from fresh Animals tissue blocks of the brain using a vibratome. After 1 h of Animals employed in this study were 7- to 8-week-old fe- recovery time in a chamber containing oxygenated artifi- male mice, C57BL/6N, obtained from Charles-River (Italy) cial cerebrospinal fluid (ACSF), single slices were trans- and CNR-EMMA Mouse Clinic facility (Monterotondo- ferred to a recording chamber and submerged in a Rome, Italy). Animals were randomly assigned to standard continuously flowing ACSF at 2–3 ml/min gassed with cages, with 4–5 animals per cage, and kept under standard 95% O2–5% CO2. The composition of the ACSF was (in housing conditions with a light/dark cycle of 12 h and free mM): 126 NaCl, 2.5 KCl, 1.2 MgCl2, 1.2 NaH2PO4, 2.4 access to food and water. Minipump-implanted mice were CaCl2, 11 glucose, and 25 NaHCO3. Purkinjie cells (PCs) housed in individual cages endowed with special bedding could be easily identified using an Olympus BX50WI up- (TEK-FRESCH, Harlan) in order to avoid skin infections right microscope with a ×40 water-immersion objective around the surgical scar. combined with an infrared filter. Whole-cell patch- Experiments were carried out in accordance with the clamp recordings were made with borosilicate glass Internal Institutional Review Committee, the European pipettes (1.8 mm outer diameter; 2–5.5 MΩ) in voltage- Directive 2010/63/EU and the European Recommenda- clamp mode at the holding potential of − 70 mV. To tions 526/2007, and the Italian D.Lgs 26/2014. All efforts detect spontaneous excitatory postsynaptic currents were made to minimize the number of animals used, as (sEPSCs), the recording pipettes were filled with internal well as their suffering. solution containing
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