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

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• 作者：Yu-Ting Tseng^a ; ^b ; Cheng-Sheng Chen^c ; ^e ; Yuh-Jyh Jong^d ; ^f ; ^g ; Fang-Rong Chang^a ; Yi-Ching Lo^a ; ^b ; ^d ; ^{yichlo@kmu.edu.tw" class="auth_mail" title="E-mail the corresponding author}
• 关键词：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 f
• 刊名：Pharmacological Research
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：111
• 期：Complete
• 页码：58-75
• 全文大小：7676 K

文摘

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 (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.