title: Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms.
abstract: Spinal muscular atrophy (SMA) is a devastating genetic motoneuron disease leading to infant death. No effective therapy is currently available. It has been suggested that β-lactam antibiotics such as ceftriaxone may offer neuroprotection in motoneuron diseases. Here, we investigate the therapeutic effect of ceftriaxone in a murine model of SMA. Treated animals present a modest, but significant ameliorated neuromuscular phenotype and increased survival, which correlate with protection of neuromuscular units. Whole gene expression profiling in treated mice demonstrates modifications in several genes including those involved in RNA metabolism toward wild-type. The neuroprotective effect seems to be mediated by multiple mechanisms that encompass the increase of the glutamate transporter Glt1, the transcription factor Nrf2, as well as SMN protein. This study provides the first evidence of a potential positive effect of this class of molecules in SMA. Further investigation of analogs with increased and more specific therapeutic effects warrants the development of useful therapies for SMA.
authors.affiliation: Dino Ferrari Centre, Department of Neurological Sciences, University of Milan, IRCCS Foundation Ca' Granda, Ospedale Maggiore Policlinico, Milan, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Nizzardo
authors.forename: Martina
authors.initials: M
authors.lastname: Nardini
authors.forename: Dario
authors.initials: D
authors.lastname: Ronchi
authors.forename: Sabrina
authors.initials: S
authors.lastname: Salani
authors.forename: Chiara
authors.initials: C
authors.lastname: Donadoni
authors.forename: Francesco
authors.initials: F
authors.lastname: Fortunato
authors.forename: Giorgia
authors.initials: G
authors.lastname: Colciago
authors.forename: Marianna
authors.initials: M
authors.lastname: Falcone
authors.forename: Chiara
authors.initials: C
authors.lastname: Simone
authors.forename: Giulietta
authors.initials: G
authors.lastname: Riboldi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Govoni
authors.forename: Nereo
authors.initials: N
authors.lastname: Bresolin
authors.forename: Giacomo P
authors.initials: GP
authors.lastname: Comi
authors.forename: Stefania
authors.initials: S
authors.lastname: Corti
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015153:Blotting, Western; D002443:Ceftriaxone / Q000494:pharmacology / Q000627:therapeutic use*; D002452:Cell Count; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055532:SMN Complex Proteins / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D018696:Neuroprotective Agents; D055532:SMN Complex Proteins; D002443:Ceftriaxone