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.