Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation.

摘要: The identification of novel molecular targets crucially involved in motor neuron degeneration/survival is a necessary step for the development hopefully more effective therapeutic strategies amyotrophic lateral sclerosis (ALS) patients. In this view, S1R, an endoplasmic reticulum (ER)-resident receptor with chaperone-like activity, has recently attracted great interest. S1R several processes leading to acute and chronic neurodegeneration, including ALS pathology. Treatment agonist PRE-084 improves locomotor function survival presymptomatic early symptomatic mutant SOD1-G93A mice. Here, we tested efficacy model spontaneous degeneration, wobbler mouse (wr) as proof concept that may be regarded key target also cases not linked SOD1 mutation. Increased staining was detectable morphologically spared cervical spinal cord neurons wr mice both at (6th week) late (12th phases clinical progression. signal hypertrophic astrocytes reactive microglia Chronic treatment (three times week, 8weeks), starting symptom onset, significantly increased levels BDNF gray matter, improved ameliorated paw abnormality grip strength performance. addition, reduced number whereas, CD11b+ microglial cells increased. A deeper evaluation markers revealed significant positive pan-macrophage marker CD68 CD206+ cells, tissue restoration, white matter PRE-084-treated mRNA TNF-α IL-1β were affected by treatment. Thus, our results support pharmacological manipulation promising strategy cure point availability growth factors modulation astrocytosis macrophage/microglia part mechanisms S1R-mediated neuroprotection.