Nonantibiotic Properties of Tetracyclines: Structural Basis for Inhibition of Secretory Phospholipase A2

Dalm, Daniela; Palm, Gottfried J.; Aleksandrov, Alexey; Simonson, Thomas; Hinrichs, W.

doi:10.1016/j.jmb.2010.02.049

Cited by 29 publications

(21 citation statements)

References 48 publications

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“…Tetracyclines, including doxycycline, have previously been associated with modulation of secretory phospholipases ( 84,85 ) as well as the inhibition of metalloproteinases, downregulation of cytokines, and cell proliferation ( 86 ), all of which should be considered in regard to the phenotypic characterization of the Barth syndrome mouse model. Because the inducible Taz KD mice were compared with wild-type age-matched littermates also fed a doxycycline-enriched diet, the differential phenotype displayed represents the pathological changes induced by cardiac myocyte tafazzin defi ciency.…”

Section: Discussionmentioning

confidence: 99%

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Kiebish

Yang

Liu

et al. 2013

Journal of Lipid Research

105

116

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Section: Discussionmentioning

confidence: 99%

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Kiebish

Yang

Liu

et al. 2013

Journal of Lipid Research

105

116

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“…Decreased inflammatory loading could contribute to decreased osteopenia and inflammatory risk markers in CHD, DM and arthritis, considering the prevalence of common markers for disease progression across these entities and periodontitis [46, 83, 84, 92, 109, 122, 123] and [128]. SDD is a more potent inhibitor of MMPs than tetracycline; and safer than minocycline with superior pharmacokinetics which favor patient compliance.…”

Section: Summary and Discussionmentioning

confidence: 99%

“…The results of two previous open trials and three double-blind controlled studies indicate that early administration of minocycline could be beneficial to subjects with RA, or those with mild disease [128]; in the context of joint swelling, tenderness, laboratory parameters and patient assessments. These beneficial effects were confirmed in a meta-analysis summarizing clinical trials that had been conducted until then [123].…”

Section: Potential Adjunctive Role Of Tetracyclines In Ra and Periodomentioning

confidence: 99%

Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities

Tilakaratne¹,

Soory²

2014

TODENTJ

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The non-antimicrobial properties of tetracyclines such as anti-inflammatory, proanabolic and anti-catabolic actions make them effective pharmaceuticals for the adjunctive management of chronic inflammatory diseases. An over-exuberant inflammatory response to an antigenic trigger in periodontitis and other chronic inflammatory diseases could contribute to an autoimmune element in disease progression. Their adjunctive use in managing periodontitis could have beneficial effects in curbing excessive inflammatory loading from commonly associated comorbidities such as CHD, DM and arthritis. Actions of tetracyclines and their derivatives include interactions with MMPs, tissue inhibitors of MMPs, growth factors and cytokines. They affect the sequence of inflammation with implications on immunomodulation, cell proliferation and angiogenesis; these actions enhance their scope, in treating a range of disease entities. Non-antimicrobial chemically modified tetracyclines (CMTs) sustain their diverse actions in organ systems which include anti-inflammatory, anti-apoptotic, anti-proteolytic actions, inhibition of angiogenesis and tumor metastasis. A spectrum of biological actions in dermatitis, periodontitis, atherosclerosis, diabetes, arthritis, inflammatory bowel disease, malignancy and prevention of bone resorption is particularly relevant to minocycline. Experimental models of ischemia indicate their specific beneficial effects. Parallel molecules with similar functions, improved Zn binding and solubility have been developed for reducing excessive MMP activity. Curbing excessive MMP activity is particularly relevant to periodontitis, and comorbidities addressed here, where specificity is paramount. Unique actions of tetracyclines in a milieu of excessive inflammatory stimuli make them effective therapeutic adjuncts in the management of chronic inflammatory disorders. These beneficial actions of tetracyclines are relevant to the adjunctive management of periodontitis subjects presenting with commonly prevalent comorbidities addressed here.

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“…A number of studies in mice have shown that induced proinflammatory cytokines such as TNF-α decline with minocycline treatment [38,41], perhaps by inhibition of the p38 mitogen-activated protein kinase (p38 MAPK) pathway. Among other possibilities suggested for minocycline action are down-regulation of major histocompatibility complex II expression through interferon regulatory factor 1 (IRF-1) and protein kinase C α/βII (PKC α/βII ) inhibition [52], inhibition of secretory phospholipase A 2 indicated by structural studies [53], neuroprotection by direct scavenging of peroxynitrite [54] and reduction of several other inflammatory factors [55]. …”

Section: Discussionmentioning

confidence: 99%

Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression

Kay

Palmer

2013

J Neuroinflammation

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BackgroundThe neuronal ceroid lipofuscinoses (NCLs; or Batten disease) are fatal inherited human neurodegenerative diseases affecting an estimated 1:12,500 live births worldwide. They are caused by mutations in at least 11 different genes. Currently, there are no effective treatments. Progress into understanding pathogenesis and possible therapies depends on studying animal models. The most studied animals are the CLN6 South Hampshire sheep, in which the course of neuropathology closely follows that in affected children. Neurodegeneration, a hallmark of the disease, has been linked to neuroinflammation and is consequent to it. Activation of astrocytes and microglia begins prenatally, starting from specific foci associated with the later development of progressive cortical atrophy and the development of clinical symptoms, including the occipital cortex and blindness. Both neurodegeneration and neuroinflammation generalize and become more severe with increasing age and increasing clinical severity. The purpose of this study was to determine if chronic administration of an anti-inflammatory drug, minocycline, from an early age would halt or reverse the development of disease.MethodMinocycline, a tetracycline family antibiotic with activity against neuroinflammation, was tested by chronic oral administration of 25 mg minocycline/kg/day to presymptomatic lambs affected with CLN6 NCL at 3 months of age to 14 months of age, when clinical symptoms are obvious, to determine if this would suppress neuroinflammation or disease progression.ResultsMinocycline was absorbed without significant rumen biotransformation to maintain pharmacological concentrations of 1 μM in plasma and 400 nM in cerebrospinal fluid, but these did not result in inhibition of microglial activation or astrocytosis and did not change the neuronal loss or clinical course of the disease.ConclusionOral administration is an effective route for drug delivery to the central nervous system in large animals, and model studies in these animals should precede highly speculative procedures in humans. Minocycline does not inhibit a critical step in the neuroinflammatory cascade in this form of Batten disease. Identification of the critical steps in the neuroinflammatory cascade in neurodegenerative diseases, and targeting of specific drugs to them, will greatly increase the likelihood of success.

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Nonantibiotic Properties of Tetracyclines: Structural Basis for Inhibition of Secretory Phospholipase A2

Cited by 29 publications

References 48 publications

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Dysfunctional cardiac mitochondrial bioenergetic, lipidomic, and signaling in a murine model of Barth syndrome

Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities

Chronic oral administration of minocycline to sheep with ovine CLN6 neuronal ceroid lipofuscinosis maintains pharmacological concentrations in the brain but does not suppress neuroinflammation or disease progression

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