title: Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease characterized by motor neurons degeneration and muscular atrophy. There is no effective SMA treatment. Loganin is a botanical candidate with anti-inflammatory, anti-oxidant, glucose-lowering and anti-diabetic nephropathy activities. The aim of this study is to investigate the potential protective effects of loganin on SMA using two cellular models, SMN-deficient NSC34 cells and SMA patient fibroblasts, and an animal disease model, SMAΔ7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3β, p-CREB, BDNF and Bcl-2. However, both AG1024 (IGF-1 R antagonist) and IGF-1 R siRNA attenuated the protective effects of loganin on SMN level and cell viability in SMN-deficient NSC34 cells. In SMA patient fibroblasts, loganin up-regulated levels of SMN, FL-SMN2, and Gemins, increased numbers of SMN-containing nuclear gems, modulated splicing factors, and up-regulated p-Akt. Furthermore, in the brain, spinal cord and gastrocnemius muscle of SMAΔ7 mice, loganin up-regulated the expressions of SMN and p-Akt. Results from righting reflex and hind-limb suspension tests indicated loganin improved muscle strength of SMAΔ7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAΔ7 mice. Loganin also increased body weight, but the average lifespan of loganin (20mg/kg/day)-treated SMA mice was 16.80±0.73 days, while saline-treated SMA mice was 10.91±0.96 days. In conclusion, the present results demonstrate that loganin provides benefits to SMA therapeutics via improving SMN restoration, muscle strength and body weight. IGF-1 plays an important role in loganin neuroprotection. Loganin can be therefore a valuable complementary candidate for treatment of neuromuscular diseases via regulation of muscle protein synthesis and neuroprotection.
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Tseng
authors.affiliation: Department of Psychiatry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Psychiatry, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Cheng-Sheng
authors.initials: CS
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Departments of Pediatrics and Laboratory Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan.
authors.forename: Yuh-Jyh
authors.initials: YJ
authors.lastname: Jong
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan.
authors.forename: Fang-Rong
authors.initials: FR
authors.lastname: Chang
authors.affiliation: Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Department of Pharmacology, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. Electronic address: yichlo@kmu.edu.tw.
authors.forename: Yi-Ching
authors.initials: YC
authors.lastname: Lo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D019610:Cytoprotection; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D039823:Iridoids / Q000494:pharmacology*; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D009124:Muscle Proteins / Q000378:metabolism; D053580:Muscle Strength / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D009154:Mutation; D009410:Nerve Degeneration; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010641:Phenotype; D010766:Phosphorylation; D014176:Protein Biosynthesis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D055533:Survival of Motor Neuron 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D000070584:Tripartite Motif Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D039823:Iridoids; D009124:Muscle Proteins; D018696:Neuroprotective Agents; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D000070584:Tripartite Motif Proteins; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C059516:loganin
keywords: Akt/mTOR; IGF-1; Loganin; Muscular atrophy; Neuroprotection; Survival motor neuron protein