Actions of the antihistaminergic clemastine on presymptomatic SOD1-G93A mice ameliorate ALS disease progression

摘要: Amyotrophic lateral sclerosis (ALS) is a disease with strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. However, how successfully balance neuroprotective versus neurotoxic actions the use of antinflammatory agents still under scrutiny. We have recently shown that antihistamine clemastine, an FDA-approved drug, can influence M1/M2 switch occurring in SOD1-G93A ALS microglia. Here, we chronically treated female mice evaluated progression and performed lumbar spinal cord analysis at symptomatic end stage disease. Moreover, studied mechanism action clemastine primary adult cultures NSC-G93A motor neuron-like cells. found short treatment (50 mg/kg) from asymptomatic (postnatal day 40) phase 120) significantly delayed onset extended survival about 10 %. Under these conditions, induced protection neurons, modulation inflammatory parameters, reduction SOD1 protein levels SQSTM1/p62 autophagic marker, when analysed immediately 120). A long (from until stage) instead failed ameliorate progression. At disease, decreased microgliosis increased LC3-II while produced opposite effects. Finally, stimulated flux via mTOR signalling pathway levels. Modulation autophagy was also demonstrated NSC34 By gaining insights into ameliorating antihistaminergic compound our findings might represent exploitable therapeutic approach for familial forms ALS.