title: Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression.
abstract: Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how to successfully balance neuroprotective versus neurotoxic actions by the use of antinflammatory agents is still under scrutiny. We have recently shown that the antihistamine clemastine, an FDA-approved drug, can influence the M1/M2 switch occurring in SOD1-G93A ALS microglia.
  
  
  
  Here, we have chronically treated female SOD1-G93A mice with clemastine, evaluated disease progression and performed mice lumbar spinal cord analysis at symptomatic and end stage of the disease. Moreover, we have studied the mechanism of action of clemastine in primary adult spinal SOD1-G93A microglia cultures and in NSC-G93A motor neuron-like cells.
  
  
  
  We found that a short treatment with clemastine (50 mg/kg) from asymptomatic (postnatal day 40) to symptomatic phase (postnatal day 120) significantly delayed disease onset and extended the survival of SOD1-G93A mice by about 10 %. Under these conditions, clemastine induced protection of motor neurons, modulation of inflammatory parameters, reduction of SOD1 protein levels and SQSTM1/p62 autophagic marker, when analysed immediately at the end of the treatment (postnatal day 120). A long treatment with clemastine (from asymptomatic until the end stage) instead failed to ameliorate ALS disease progression. At the end stage of the disease, we found that clemastine short treatment decreased microgliosis and SOD1 protein and increased LC3-II autophagic marker, while the long treatment produced opposite effects. Finally, in spinal microglia cultures from symptomatic SOD1-G93A mice clemastine activated inflammatory parameters, stimulated autophagic flux via the mTOR signalling pathway and decreased SOD1 levels. Modulation of autophagy was also demonstrated in NSC34 SOD1-G93A motor neuron-like cells.
  
  
  
  By gaining insights into the ameliorating actions of an antihistaminergic compound in ALS disease, our findings might represent an exploitable therapeutic approach for familial forms of ALS.
authors.affiliation: Santa Lucia Foundation, IRCCS, Rome, Italy.|Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy.
authors.forename: Savina
authors.initials: S
authors.lastname: Apolloni
authors.affiliation: Santa Lucia Foundation, IRCCS, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Fabbrizio
authors.affiliation: Santa Lucia Foundation, IRCCS, Rome, Italy.|Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy.
authors.forename: Susanna
authors.initials: S
authors.lastname: Amadio
authors.affiliation: Santa Lucia Foundation, IRCCS, Rome, Italy. cinzia.volonte@cnr.it.|Institute of Cell Biology and Neurobiology, CNR, Via del Fosso di Fiorano, 65, 00143, Rome, Italy. cinzia.volonte@cnr.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Volonté
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000831:Animals, Newborn; D058070:Asymptomatic Diseases / Q000628:therapy; D001343:Autophagy / Q000187:drug effects; D002478:Cells, Cultured; D002974:Clemastine / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D006633:Histamine Antagonists / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000473:pathology; D058848:Receptors, Purinergic P2X4 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D016207:Cytokines; D006633:Histamine Antagonists; D058848:Receptors, Purinergic P2X4; D002974:Clemastine; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase
keywords: Antihistamine; Autophagy; Neuroinflammation; Primary adult microglia; Spinal cord