N-Phenacylthiazolium Bromide Reduces Bone Fragility Induced by Nonenzymatic Glycation

Abstract

Nonenzymatic glycation (NEG) describes a series of post-translational modifications in the collagenous matrices of human tissues. These modifications, known as advanced glycation end-products (AGEs), result in an altered collagen crosslink profile which impacts the mechanical behavior of their constituent tissues. Bone, which has an organic phase consisting primarily of type I collagen, is significantly affected by NEG. Through constant remodeling by chemical resorption, deposition and mineralization, healthy bone naturally eliminates these impurities. Because bone remodeling slows with age, AGEs accumulate at a greater rate. An inverse correlation between AGE content and material-level properties, particularly in the post-yield region of deformation, has been observed and verified. Interested in reversing the negative effects of NEG, here we evaluate the ability of n-phenacylthiazolium bromide (PTB) to cleave AGE crosslinks in human cancellous bone. Cancellous bone cylinders were obtained from nine male donors, ages nineteen to eighty, and subjected to one of six PTB treatments. Following treatment, each specimen was mechanically tested under physiological conditions to failure and AGEs were quantified by fluorescence. Treatment with PTB showed a significant decrease in AGE content versus control NEG groups as well as a significant rebound in the post-yield material level properties (p<0.05). The data suggest that treatment with PTB could be an effective means to reduce AGE content and decrease bone fragility caused by NEG in human bone.

Staphylococcus aureus Biofilm Inhibiting Activity of Advanced Glycation Endproduct Crosslink Breaking and Glycation Inhibiting Compounds

“…The crosslink breaking abilities of PTB have been demonstrated in both in vitro and in vivo studies [ 47 ]. PTB has shown effectiveness in breaking down AGEs and preventing their accumulation in vascular tissues [ 26 ], lens proteins [ 48 ], periodontic tissue [ 49 ] and bone [ 50 ]. No antibacterial or antibiofilm properties of PTB have not been reported at this time, although a significant growth inhibitory effect was observed at sufficiently high concentrations.…”

Advanced Glycation End Products: New Clinical and Molecular Perspectives

“…These are the N -phenacylthiazolium bromide (PTB) [ 172 ] with its derivative ALT-711 or alagebrium (dimethyl-3- N -phenacylthiazolium chloride) [ 173 ], given their ability to cleave AGE-AGE crosslinks that maintain AGEs attached to tissue proteins like collagen and elastin [ 174 ]. Thoroughly, their precise mechanisms of action rely on their reactions to carbonyl groups located in the crosslinks between AGEs, subsequently promoting the spontaneous cleavage of carbon–carbon bonds at physiologic pH [ 175 ]. Likewise, an experimental study demonstrated the efficacy of MnmC, an enzyme involved in bacterial tRNA modification, capable of performing a catalytic reversion of the AGEs carboxyethyl-lysine (CEL) and carboxymethyl-lysine (CML) to lysine’s native structure [ 176 ].…”

Effect of type 2 diabetes-related non-enzymatic glycation on bone biomechanical properties

“…One study showed that whereas aminoguanidine treatment reduced the pentosidine content induced by in vitro glycation of bovine cortical bone, it did not influence hardness assessed by microindentation or mechanical properties assessed by 3-point bending [59]. In contrast, a recent study showed that human cancellous bone specimens treated with PTB in vitro resulted in decreased AGE content and a corresponding increase in ductility (e.g., post-yield strain) [60]. It has also been shown that vitamin B6 inhibits AGEs [61, 62].…”