title: Chronic treatment with lithium does not improve neuromuscular phenotype in a mouse model of severe spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by defective levels of the survival motor neuron (SMN) protein. SMA causes spinal motoneuron (MN) loss, and progressive muscle weakness and paralysis. Currently, there is no effective therapy to cure this disease. Although different strategies focused on increasing the expression of functional SMN protein have been assayed, numerous SMN-independent therapeutic approaches have been demonstrated to have potential effectiveness in improving the SMA phenotype in mouse models and clinical trials. Recent works have shown that compounds which inhibit GSK-3β activity are effective in promoting MN survival and ameliorating lifespan in models of MN diseases including SMA. Taking into account the reported neuroprotective actions of lithium (Li) through the inhibition of GSK-3β in different studies, we tested here its potential efficiency as a therapeutic agent in a mouse model of severe SMA (SMNΔ7 mice). We show that the chronic treatment with Li initiated before the appearance of disease symptoms, although inhibited GSK-3β, did not improve the median survival, motor behavior, and spinal MN loss linked to SMA. Li administration did not either ameliorate the microglial and astroglial reaction in the spinal cord or the depletion of glutamatergic synapses on MNs observed in SMNΔ7 animals. Moreover, Li treatment did not mitigate muscle atrophy or calcitonin gene-related peptide (CGRP) downregulation in the neuromuscular junctions linked to the disease. However, a significant reduction in apoptotic cell death found in the skeletal muscle of SMA mice was observed after Li treatment.
authors.affiliation: Unitat de Neurobiologia Cel·lular, Departament de Medicina Experimental, Facultat de Medicina, Universitat de Lleida and Institut de Recerca Biomèdica de Lleida (IRBLLEIDA), Av. Rovira Roure 80, 25198 Lleida, Catalonia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Dachs
authors.forename: L
authors.initials: L
authors.lastname: Piedrafita
authors.forename: M
authors.initials: M
authors.lastname: Hereu
authors.forename: J E
authors.initials: JE
authors.lastname: Esquerda
authors.forename: J
authors.initials: J
authors.lastname: Calderó
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002452:Cell Count; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018021:Lithium Chloride / Q000097:blood / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000096:biosynthesis / Q000235:genetics; D010641:Phenotype; D004856:Postural Balance / Q000235:genetics / Q000502:physiology; D011597:Psychomotor Performance / Q000187:drug effects; D012018:Reflex / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000502:physiology
chemical_list: C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride
keywords: ALS; ANOVA; CGRP; FL; GFAP; GSK-3β; Iba1; Li; LiCl; MN; N-methyl-d-aspartate; NMDA; PB; PBS; PI3K; RT; SMA; SMN; SMNΔ7 mouse; SOD1; TA; TBST; TUNEL; Tween 20–Tris-buffered saline; VGluT1; amyotrophic lateral sclerosis; analysis of variance; calcitonin gene-related peptide; full-length; glial fibrillary acidic protein; glycogen synthase kinase-3β; ionized calcium-binding adaptor molecule 1; lithium; lithium chloride; motoneuron; phosphate buffer; phosphate-buffered saline; phosphatidylinositol 3-kinase; room temperature; skeletal muscle; spinal cord; spinal muscular atrophy; superoxide dismutase 1; survival motor neuron; terminal deoxynucleotidyl transferase dUTP nick-end labeling; tibialis anterior; vesicular glutamate transporter 1