Histone Deacetylase Inhibition Activity and Molecular Docking of (E )-Resveratrol: Its Therapeutic Potential in Spinal Muscular Atrophy

DAYANGAÇ ERDEN D., BORA G., Ayhan P., Kocaefe C., DALKARA S., YELEKÇİ K., ...Daha Fazla

CHEMICAL BIOLOGY & DRUG DESIGN, cilt.73, sa.3, ss.355-364, 2009 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 73 Sayı: 3
  • Basım Tarihi: 2009
  • Doi Numarası: 10.1111/j.1747-0285.2009.00781.x
  • Dergi Adı: CHEMICAL BIOLOGY & DRUG DESIGN
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.355-364
  • Anahtar Kelimeler: (E )-resveratrol, molecular docking, SMN2, spinal muscular atrophy, INCREASES SMN EXPRESSION, VALPROIC ACID INCREASES, SURVIVAL MOTOR-NEURON, IN-VITRO, OXIDATIVE STRESS, PROTEIN-LEVEL, MOUSE MODEL, RESVERATROL, GENE, PHENYLBUTYRATE
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

Spinal muscular atrophy is an autosomal recessive motor neuron disease that is caused by mutation of the survival motor neuron gene (SMN1) but all patients retain a nearly identical copy, SMN2. The disease severity correlates inversely with increased SMN2 copy. Currently, the most promising therapeutic strategy for spinal muscular atrophy is induction of SMN2 gene expression by histone deacetylase inhibitors. Polyphenols are known for protection against oxidative stress and degenerative diseases. Among our candidate prodrug library, we found that (E )-resveratrol, which is one of the polyphenolic compounds, inhibited histone deacetylase activity in a concentration-dependent manner and half-maximum inhibition was observed at 650 mu m. Molecular docking studies showed that (E )-resveratrol had more favorable free energy of binding (-9.09 kcal/mol) and inhibition constant values (0.219 mu m) than known inhibitors. To evaluate the effect of (E )-resveratrol on SMN2 expression, spinal muscular atrophy type I fibroblast cell lines was treated with (E )-resveratrol. The level of full-length SMN2 mRNA and protein showed 1.2- to 1.3-fold increase after treatment with 100 mu m (E )-resveratrol in only one cell line. These results indicate that response to (E )-resveratrol treatment is variable among cell lines. This data demonstrate a novel activity of (E )-resveratrol and that it could be a promising candidate for the treatment of spinal muscular atrophy.