title: Laquinimod prevents inflammation-induced synaptic alterations occurring in experimental autoimmune encephalomyelitis.
abstract: BACKGROUND
  There are two generally accepted strategies for treating multiple sclerosis (MS), preventing central nervous system (CNS) damage indirectly through immunomodulatory interventions and/or repairing CNS damage by promoting remyelination. Both approaches also provide neuroprotection since they can prevent, indirectly or directly, axonal damage.
  
  
  OBJECTIVE
  Recent experimental and clinical evidence indicates that the novel immunomodulatory drug laquinimod can exert a neuroprotective role in MS. Whether laquinimod-mediated neuroprotection is exerted directly on neuronal cells or indirectly via peripheral immunomodulation is still unclear.
  
  
  METHODS
  C57Bl/6 experimental autoimmune encephalomyelitis (EAE) mice, immunised with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide, were treated for 26 days with subcutaneous daily injections of laquinimod (from 1 to 25 mg/kg). Patch clamp electrophysiology was performed on acute brain striatal slices from EAE mice treated with daily (25 mg/kg) laquinimod and on acute brain striatal slices from control mice bathed with laquinimod (1-30 µM).
  
  
  RESULTS
  Both preventive and therapeutic laquinimod treatment fully prevented the alterations of GABAergic synapses induced by EAE, the first limiting also glutamatergic synaptic alterations. This dual effect might, in turn, have limited glutamatergic excitotoxicity, a phenomenon previously observed early during EAE and possibly correlated with later axonal damage. Furthermore, laquinimod treatment also preserved cannabinoid CB1 receptor sensitivity, normally lost during EAE. Finally, laquinimod per se was able to regulate synaptic transmission by increasing inhibitory post-synaptic currents and, at the same time, reducing excitatory post-synaptic currents.
  
  
  CONCLUSIONS
  Our data suggest a novel neuroprotective mechanism by which laquinimod might in vivo protect from neuronal damage occurring as a consequence of inflammatory immune-mediated demyelination.
authors.affiliation: Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Hospital, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Ruffini
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Andrea
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Elena
authors.initials: E
authors.lastname: Brambilla
authors.forename: Annamaria
authors.initials: A
authors.lastname: Finardi
authors.forename: Caterina
authors.initials: C
authors.lastname: Motta
authors.forename: Valeria
authors.initials: V
authors.lastname: Studer
authors.forename: Francesca
authors.initials: F
authors.lastname: Barbieri
authors.forename: Valentina
authors.initials: V
authors.lastname: De Chiara
authors.forename: Liat
authors.initials: L
authors.lastname: Hayardeny
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology*; D005260:Female; D007249:Inflammation / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D015363:Quinolones / Q000494:pharmacology*; D013569:Synapses / Q000187:drug effects* / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D015363:Quinolones; C476223:laquinimod