S-Allylmercapto-N-Acetylcysteine Protects Caenorhabditis Elegans and Cultured Stromal Bone Marrow Cells from Oxidative Stress and Improves Bone Microarchitecture of Healthy and Diabetic Mice

We have previously shown that S-allylmercapto-N-acetylcysteine (ASSNAC) activates Nrf2-mediated processes, increasing reduced glutathione (GSH) cellular level and resistance to oxidation in cultured endothelial cells (Izigov et al., FRBM 50:1131, 2011). In the present study we further explored the antioxidant protective effect of ASSNAC in Caenorhabditis elegans (C. elegans) , in cultured stromal bone marrow cells (SBMC) and on the bone microarchitecture of adult female healthy and obese/diabetic mice. ASSNAC treatment (2 mM; 24 hr) of C. elegans significantly increased Glutathione S-Transferase gene expression (10-fold) and GSH content (2.6-fold), decreased C. elegans death following exposure to H 2 O 2 (3.5 mM; 120 min) from 88% down to 8%, and significantly increased the mean lifespan compared to control (26.45 ± 0.64 versus 22.90 ± 0.59 days; log-rank p ≤ 0.001) with maximum lifespan of 40 versus 36 days. ASSNAC treatment (0.2 mM; 24 hr) of SBMC significantly increased GSH level (2-fold) and resistance to cytotoxic effect of glycated albumin. Adult healthy female mice treated with ASSNAC (50 mg/kg/day for 8 weeks) demonstrated significant increase in SBMC number (160%), percentage of CD73 + /CD45 - mesenchymal stem cells (234%) and GSH level (210%) in the bone marrow. Micro-Computed Tomography (μCT) of the femur from these mice demonstrated significant increase in: femur length (3%), diameter (3%) and moment of inertia [13% (polar), 11% (areal)]. Similar ASSNAC treatment of obese/diabetic mice (C57BLKS/J Lepr db+/+ ) demonstrated significant increase in femur length (5%), cortical thickness (17%), trabecular bone volume fraction (BV/TV; 107%), trabecular number (81%) and connectivity (100%) and in more plate-like trabecular structures. In conclusion, these experiments demonstrate that ASSNAC is an Nrf2-inducing molecule protecting the entire organism ( C. elegans ) from oxidative stress and extending its lifespan. Furthermore, ASSNAC protects bones from oxidative stress associated osteoporosis and may improve bone mechanical strength [based on the improved cortical moment of inertia] in adult healthy and to more extend in obese/diabetic mice.