Abstract
BackgroundAmyotrophic 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.MethodsHere, 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.ResultsWe 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.ConclusionsBy 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.
Highlights
Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death
Altered macroautophagy is reported in the spinal cord of superoxide dismutase 1 (SOD1) mutant mice [7] and autophagy overexpression is proved in motor neurons of ALS mice by in vivo optical imaging [8]; inefficient autophagosomelysosome fusion is reported in ALS patients [9, 10] to the point that a strategy in modulating autophagic flux may have a promise in ALS treatment [11, 12]
Clemastine short treatment prolongs survival in SOD1-G93A mice In order to improve the potential of clemastine in ameliorating ALS disease progression, we performed two different treatments with a high dose of clemastine (50 mg/kg) in SOD1-G93A mice, both starting at postnatal day 40 (PND) but ending at either PND 120 or the end stage of the disease (Fig. 1a)
Summary
Amyotrophic lateral sclerosis (ALS) is a disease with a strong neuroinflammatory component sustained by activated microglia contributing to motoneuron death. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by selective loss of upper and lower motor neurons and with a marked multifactorial nature where genetic factors and dysregulation of crucial molecular pathways contribute to disease pathogenesis [1]. Mutated SOD1 gene can acquire both gain and loss of function deleterious mutations that modify SOD1 activity, leading to the accumulation of highly toxic intracellular aggregates and becoming one of the mechanisms sustaining ALS aetiopathogenesis together with the well-known neuroinflammation [1,2,3,4]. Emerging evidence has recently suggested the occurrence of the main degradative mechanism of misfolded proteins, autophagy [5], in the pathogenesis of ALS [6]. Autophagy constitutes a physiological mechanism to degrade proteins that is generally beneficial for cells, if uncontrolled, it may be extremely harmful for neuronal survival [6]
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