Histone deacetylase inhibitors and periodontal bone loss.

BACKGROUND AND OBJECTIVE: Bone loss caused by enhanced osteoclast activity is a significant feature of periodontitis. Histone deacetylase inhibitors (HDACi) can suppress osteoclast-mediated bone loss in vitro and in vivo. This study investigated whether HDACi can suppress bone loss in experimental periodontitis. MATERIAL AND METHODS: Experimental periodontitis was induced in mice by oral inoculation with Porphyromonas gingivalis bacteria. Mice were treated orally with olive oil alone, with olive oil and a novel compound - 1179.4b - which targets both Class I and Class II histone deacetylases (HDACs) or with olive oil and MS-275, which targets Class I HDACs. Micro-computed tomography scans of live mice, stereo imaging and histological analyses were used to detect changes in bone. RESULTS: In the absence of treatment there was a 13.2% increase in bone volume in controls compared with a 7.4% decrease in P. gingivalis-inoculated mice. 1179.4b significantly reduced bone loss, with a 3.4% increase in bone volume (p < 0.01). MS-275 did not have a significant effect on P. gingivalis-induced bone loss. Histological analysis revealed that 1179.4b reduced bone loss despite having no effect on inflammation. CONCLUSION: HDACi were found to effectively suppress bone loss in the mouse model of periodontitis. 1179.4b - the inhibitor of Class I and Class II HDACs - was more effective at suppressing bone loss than MS-275, which targets Class I HDACs only. These compounds may therefore have the potential to be used for the management of periodontitis.

Zinc monoglycerolate--a slow-release source of therapeutic zinc: solubilization by endogenous ligands.

A combination of 65Zn-tracer determinations, oxidative analyses for glycerol, and a bioassay for uncomplexed Zn2+ have shown that: (i) zinc monoglycerolate (ZMG) dissolves in aqueous salt solutions/physiological media by dissociation into zinc ions and glycerol, but the rate and extent of ZMG dissolution depend upon pH, and/or concentration and complexing efficiency of zinc-ligands; (ii) under physiological conditions certain ligands present in skin and blood (e.g. citrate, lactate, albumin, histidine, glutathione and other thiols and, to a lesser extent, amino acids) accelerate ZMG dissolution; and (iii) there is a general correlation between the conditional stability constants (pH 7.3, 25 degrees C) of zinc-ligand complexes and the ability of given ligands to (a) solubilize ZMG in vitro and (b) mask the irritancy of Zn2+ in vivo. These observations indicate a mechanism for the transformation of ZMG applied transdermally or subcutaneously, to bioactive zinc (anti-arthritic nutritional supplement, etc.).

Transdermal delivery of inorganic complexes as metal drugs or nutritional supplements.

The gastro-intestinal tract presents a significant barrier to the efficient absorption of both orally administered metal drugs and dietary essential trace minerals. Absorption can be compromised by competition between alimentary metal ions, by an excess of dietary ligands (e.g. polyphosphates), or by disease (e.g. chronic inflammation). Alternative delivery by injection can be expensive, painful, often promotes systemic toxicity and usually leads to rapid elimination through excretion (bile, urine), as a consequence of bolus dosing. By contrast, our new observations indicate that presenting trace metals or metal drugs in lipophilic forms which can penetrate the dermis, permits their slow release from the skin with more efficient (relative to incipient toxicity) systemic delivery. Examples are given from our own research of dermal application of copper(II), zinc(II), titanium(IV), platinum(II) and gold(I) complexes to treat chronic inflammatory disease. Some of these compounds are also anti-cancer agents. Physical and biological constraints to transdermal (percutaneous) drug delivery are discussed together with some chemical principles governing selection of complexes as metal drugs or dietary supplements.