Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy

Pharmacol Res. 2016 Sep;111:58-75. doi: 10.1016/j.phrs.2016.05.023. Epub 2016 May 27.


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.

Keywords: Akt/mTOR; IGF-1; Loganin; Muscular atrophy; Neuroprotection; Survival motor neuron protein.

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cell Line
  • Cytoprotection
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Fibroblasts / drug effects
  • Fibroblasts / enzymology
  • Fibroblasts / pathology
  • Genetic Predisposition to Disease
  • Humans
  • Insulin-Like Growth Factor I / metabolism
  • Iridoids / pharmacology*
  • Mice
  • Mice, Transgenic
  • Motor Activity / drug effects
  • Motor Neurons / drug effects*
  • Motor Neurons / enzymology
  • Motor Neurons / pathology
  • Muscle Proteins / metabolism
  • Muscle Strength / drug effects
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / enzymology
  • Muscle, Skeletal / pathology
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / enzymology
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / physiopathology
  • Mutation
  • Nerve Degeneration
  • Neuroprotective Agents / pharmacology*
  • Phenotype
  • Phosphorylation
  • Protein Biosynthesis
  • Proto-Oncogene Proteins c-akt / metabolism*
  • RNA Interference
  • SKP Cullin F-Box Protein Ligases / metabolism
  • Signal Transduction / drug effects
  • Survival of Motor Neuron 1 Protein / biosynthesis*
  • Survival of Motor Neuron 1 Protein / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Time Factors
  • Transfection
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Weight Gain / drug effects


  • Iridoids
  • Muscle Proteins
  • Neuroprotective Agents
  • Smn1 protein, mouse
  • Survival of Motor Neuron 1 Protein
  • Tripartite Motif Proteins
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Proto-Oncogene Proteins c-akt
  • loganin