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, SMA Delta 7 mice. In SMN-deficient NSC34 cells, loganin increased cell viability, neurite length, and expressions of SMN, Gemin2, SMN-Gemin2 complex, p-Akt, p-GSK-3 beta, 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 SMA Delta 7 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 SMA Delta 7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMA Delta 7 mice. Loganin also increased body weight, but the average lifespan of loganin (20 mg/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. (C) 2016 Elsevier Ltd. All rights reserved.
- Loganin; Muscular atrophy; Neuroprotection; Survival motor neuron protein; Akt/mTOR; IGF-1
- MOTOR-NEURON PROTEIN; MOUSE MODEL; DIABETIC-NEPHROPATHY; CORNI-FRUCTUS; SIGNALING PATHWAY; SINGLE NUCLEOTIDE; UBIQUITIN LIGASES; IMPROVES SURVIVAL; GENE-EXPRESSION; MUSCLE ATROPHY
Tseng, Y. T., Huang, C-S., Jong, Y-J., Chang, F-R., & Lo, Y-C. (2016). Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy. Pharmacological Research, 111, 58-75. https://doi.org/10.1016/j.phrs.2016.05.023