Loganin possesses neuroprotective properties, restores SMN protein and activates protein synthesis positive regulator Akt/mTOR in experimental models of spinal muscular atrophy. (September 2016)

• Record Type: Journal Article
• Authors: Tseng, Yu-Ting; Chen, Cheng-Sheng; Jong, Yuh-Jyh; Chang, Fang-Rong; Lo, Yi-Ching
• Is Part Of: Pharmacological research. Volume 111(2016:Sep.)
• Page Start: 58
• Page End: 75
• Publication Date: 2016-09
• Subjects: SMN survival motor neuron -- SMA spinal muscular atrophy -- Akt protein kinase B -- ERK extracellular signal-regulated kinases -- GSK-3β glycogen synthase kinase-3 beta -- CREB cAMP response element-binding protein -- Elk-1 ETS-like transcription factor -- BDNF brain-derived neurotrophic factor -- Bcl-2 B-cell lymphoma 2 -- IGF-1R insulin-like growth factor-1 receptor -- FL-SMN2 full-length SMN2 transcripts -- mTOR mammalian target of rapamycin -- MAFbx/atrogin-1 muscle atrophy F-box -- MuRF-1 muscle RING finger 1; Loganin -- Muscular atrophy -- Neuroprotection -- Survival motor neuron protein -- Akt/mTOR -- IGF-1; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2016.05.023
• Languages: English
• ISSNs: 1043-6618

Abstract

Graphical abstract: 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, SMAο7 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 SMAο7 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 SMAο7 mice; moreover, loganin activated Akt/mTOR signal and inhibited atrogin-1/MuRF-1 signal in gastrocnemius muscle of SMAο7 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.