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.

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.

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

Substances

  • 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