Neuroprotective effects of the Sigma-1 receptor (SIR) agonist PRE-084, in a mouse model of moter neuron disease not linked to SOD1 mutation

The identification of novel molecular targets crucially involved in motor neuron degeneration/survival is a necessary step for the development of hopefully more effective therapeutic strategies for amyotrophic lateral sclerosis (ALS) patients. In this view, SIR, an endoplasmic reticulum (ER)-resident receptor with chaperonelike activity, has recently attracted great interest. SIR is involved in several processes leading to acute and chronic neurodegeneration, including ALS pathology. Treatment with the SIR agonist PRE-084 improves locomotor function and motor neuron survival in presymptomatic and early symptomatic mutant SOD1-G93A ALS mice. Here, we tested the efficacy of PRE-084 in a model of spontaneous motor neuron degeneration, the wobbler mouse (wr) as a proof of concept that SIR may be regarded as a key therapeutic target also for ALS cases not linked to SOD1 mutation. Increased staining for SIR was detectable in morphologically spared cervical spinal cord motor neurons of wr mice both at early (6th week) and late (12th week) phases of clinical progression. SIR signal was also detectable in hypertrophic astrocytes and reactive microglia of wr mice. Chronic treatment with PRE-084 (three times a week, for 8 weeks), starting at symptom onset, significantly increased the levels of BDNF in the gray matter, improved motor neuron survival and ameliorated paw abnormality and grip strength performance. In addition, the treatment significantly reduced the number of reactive astrocytes whereas, that of CD11b + microglial cells was increased. A deeper evaluation of microglial markers revealed significant increased number of cells positive for the pan-macrophage marker CD68 and of CD206 + cells, involved in tissue restoration, in the white matter of PRE-084-treated mice. The mRNA levels of TIVF-alpha and IL-1 beta were not affected by PRE-084 treatment. Thus, our results support pharmacological manipulation of SIR as a promising strategy to cure ALS and point to increased availability of growth factors and modulation of astrocytosis and of macrophage/microglia as part of the mechanisms involved in SIR-mediated neuroprotection. (C) 2013 Elsevier Inc All rights reserved.