title: Neuroprotective effects of the Sigma-1 receptor (S1R) agonist PRE-084, in a mouse model of motor neuron disease not linked to SOD1 mutation.
abstract: 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, S1R, an endoplasmic reticulum (ER)-resident receptor with chaperone-like activity, has recently attracted great interest. S1R is involved in several processes leading to acute and chronic neurodegeneration, including ALS pathology. Treatment with the S1R 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 S1R may be regarded as a key therapeutic target also for ALS cases not linked to SOD1 mutation. Increased staining for S1R 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. S1R signal was also detectable in hypertrophic astrocytes and reactive microglia of wr mice. Chronic treatment with PRE-084 (three times a week, for 8weeks), 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 TNF-α and IL-1β were not affected by PRE-084 treatment. Thus, our results support pharmacological manipulation of S1R 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 S1R-mediated neuroprotection.
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", Laboratory of Cellular & Molecular Neuropharmacology, University of Pavia, Pavia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Peviani
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", Laboratory of Cellular & Molecular Neuropharmacology, University of Pavia, Pavia, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Salvaneschi
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", Laboratory of Cellular & Molecular Neuropharmacology, University of Pavia, Pavia, Italy.
authors.forename: Leonardo
authors.initials: L
authors.lastname: Bontempi
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", Laboratory of Cellular & Molecular Neuropharmacology, University of Pavia, Pavia, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Petese
authors.affiliation: Rheumatology and Translational Immunology Research Laboratories (LaRIT), Division of Rheumatology, IRCCS Policlinico S. Matteo Foundation/University of Pavia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Manzo
authors.affiliation: Department of Drug Science, Laboratory of Medicinal Chemistry, University of Pavia, Pavia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rossi
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Salmona
authors.affiliation: Department of Drug Science, Laboratory of Medicinal Chemistry, University of Pavia, Pavia, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Collina
authors.affiliation: IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bigini
authors.affiliation: Department of Biology and Biotechnology "L. Spallanzani", Laboratory of Cellular & Molecular Neuropharmacology, University of Pavia, Pavia, Italy. Electronic address: curtid@unipv.it.
authors.forename: Daniela
authors.initials: D
authors.lastname: Curti
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000627:therapeutic use*; D016472:Motor Neuron Disease / Q000188:drug therapy* / Q000235:genetics; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009457:Neuroglia / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D017480:Receptors, sigma / Q000819:agonists* / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000097605:Sigma-1 Receptor
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009025:Morpholines; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D000097605:Sigma-1 Receptor; C071738:2-(4-morpholino)ethyl-1-phenylcyclohexane-1-carboxylate; C000606291:Sod1 protein, mouse
keywords: ALS; APP; Amyloid precursor protein; Amyotrophic lateral sclerosis; BDNF; CNS; Central nervous system; ER; FTLD-MND; FUS; Fronto-temporal lobar degeneration with co-occurrence of motor neuron disease; GFAP; Glial fibrillary acidic protein; IL-1β; IL-6; IP3R; Inositol 1 4, 5-triphosphate receptor; MAM; MND; Motor neurons; N-methyl di-aspartate; NMDA; NT; Neurodegeneration; Neurotrace; PKC; Reactive gliosis; S1R; SOD1; Sigma-1 receptor; Superoxide dismutase 1; TDP-43; TGN; TNF-α; Trans-Golgi network; Transactive response-DNA binding protein 43; VAPB; VPS54; Vesicular associated protein B; Wobbler; brain derived neurotrophic factor; endoplasmic reticulum; fused in sarcoma; interleukin 1beta; interleukin 6; mitochondrion-associated ER membrane; motor neuron disease; protein kinase C; tumor necrosis factor alpha; vacuolar/vesicular protein sorting 54; wobbler; wr