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.
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.
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.
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.
Centonze D, Muzio L, Rossi S, Furlan R, Bernardi G, Martino G. The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ Nature Publishing Group. 2010;17:1083–91. CrossRef
Mandolesi G, Gentile A, Musella A, Fresegna D, De Vito F, Bullitta S, et al. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015;11:711–24.
Kaye J, Piryatinsky V, Birnberg T, Hingaly T, Raymond E, Kashi R, et al. Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A. 2016;201607843.
Mishra, Silva, Wang Y. Laquinimod decreases the activation of microglia: Potential for neuroprotection? Mult Scler 2012;18:445–446.
Jolivel V, Luessi F, Masri J, Kraus SHP, Hubo M, Poisa-Beiro L, et al. Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis. Brain England. 2013;136:1048–66. CrossRef
Stojanovic IR, Kostic M, Ljubisavljevic S. The role of glutamate and its receptors in multiple sclerosis. J Neural Transm. 2014:945–55.
Mandolesi G, Musella A, Gentile A, Grasselli G, Haji N, Sepman H, et al. Interleukin-1β alters glutamate transmission at Purkinje cell synapses in a mouse model of multiple sclerosis. J Neurosci. 2013;33:12105–21.
Gentile A, Musella A, Bullitta S, Fresegna D, De Vito F, Fantozzi R, et al. Siponimod (BAF312) prevents synaptic neurodegeneration in experimental multiple sclerosis. J Neuroinflammation. 2016;13
Cherry JD, Olschowka JA, O’Banion MK. Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation. 2014;11:1–15. CrossRef
Takayasu Y, Iino M, Takatsuru Y, Tanaka K, Ozawa S. Functions of glutamate transporters in cerebellar Purkinje cell synapses. Acta Physiol (Oxf). 2009;197:1–12. CrossRef
Lehre KP, Levy LM, Ottersen OP, Storm-Mathisen J, Danbolt NC. Differential expression of two glial glutamate transporters in the rat brain: quantitative and immunocytochemical observations. J Neurosci. 1995;15:1835–53. PubMed
Martinez-Lozada Z, Guillem AM, Robinson MB. Transcriptional Regulation of Glutamate Transporters. From Extracellular Signals to Transcription Factors. 1st ed. Adv. Pharmacol. Elsevier Inc.; 2016.
Olechowski CJ, Parmar A, Miller B, Stephan J, Tenorio G, Tran K, et al. A diminished response to formalin stimulation reveals a role for the glutamate transporters in the altered pain sensitivity of mice with experimental autoimmune encephalomyelitis (EAE). Pain. International Association for the Study of Pain. 2010;149:565–72.
Vercellino M, Merola A, Piacentino C, Votta B, Capello E, Mancardi GL, et al. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J Neuropathol Exp Neurol. 2007;66:732–9.
Rothstein JD, Patel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al. Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature England. 2005;433:73–7. CrossRef
- Laquinimod ameliorates excitotoxic damage by regulating glutamate re-uptake
Francesca De Vito
Francesca Romana Rizzo
- BioMed Central
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