Tetracyclines Inhibit Connective Tissue Breakdown by Multiple Non-Antimicrobial Mechanisms

Abstract

A seminal experiment involving a germ-free rat model of connective tissue breakdown (followed soon thereafter by a series of in vitro studies) identified an unexpected non-antimicrobial property of tetracyclines (TCs). This ability of TCs to inhibit matrix metalloproteinases (MMPs) such as collagenase was found to reflect multiple direct and indirect mechanisms of action, and to be therapeutically useful in a variety of dental (e.g., adult periodontitis) and medical (e.g., arthritis, osteoporosis, cancer) diseases. The site on the TC molecule responsible for its MMP-inhibitory activity was identified which led to the development of a series of chemically modified non-antimicrobial analogs, called CMTs, which also have therapeutic potential but do not appear to induce antibiotic side-effects. Longitudinal double-blind studies on humans with adult periodontitis have demonstrated that a sub-antimicrobial dose of doxycycline (previously reported to suppress collagenase activity in the periodontal pocket) is safe and effective and has recently been approved by the FDA as an adjunct to scaling and root planing.

Proteome analyses of the growth inhibitory effects of NCH-51, a novel histone deacetylase inhibitor, on lymphoid malignant cells

“…An immobilized pH gradient gel Immobiline DryStrip (GE Healthcare Bio-Sciences Corp.), with non-linear pH values (3)(4)(5)(6)(7)(8)(9)(10), was rehydrated with the labeled protein samples at 201C for 12 h. Isoelectric focusing was performed using IPGphor (GE Healthcare Bio-Sciences Corp.) at 201C for total 65 000 khT. Immobiline DryStrips were then equilibrated for 15 min in the buffer (6 M urea, 1.5 M Tris-HCl (pH 8.8), 30% glycerol, 2% sodium dodecyl sulfate) containing 10 mg/ml dithiothreitol and prolonged for 15 min in the same buffer containing 25 mg/ml iodoacetamide.…”

Inhibitory modulation of the mitochondrial permeability transition by minocycline

“…It has been suggested that the observed protection conferred by MC is based on its anti-inflammatory and anti-oxidant properties, including the inhibition of matrix metalloproteases [21], blockade of inducible nitric oxide synthase [22], as well as free radical scavenging activity [23]. In addition, the MC-mediated neuroprotection is associated with a blockade of caspases, inhibition of MAP kinase, and prevention of cytochrome c release [2,5,14,24].…”

Doxycycline Hyclate Protects Lipopolysaccharide-Induced Endothelial Barrier Dysfunction by Inhibiting the Activation of p38 Mitogen-Activated Protein Kinase

“…11) Doxycycline, commonly used in the form of doxycycline hyclate (DOX-h), has been shown to inhibit some matrix metalloproteinases (MMP) independently of its antimicrobial effect. 12) There is a report demonstrating that doxycycline attenuates burn-induced microvascular hyperpermeability in rats through MMP-9 inhibition. 13) It is possible that DOX-h has the potential to protect vascular endothelial barrier function from LPS damage.…”