Calcium-dependent potentiation of the pro-inflammatory functions of human neutrophils by tigecycline in vitro

Cockeran, Riana; Mutepe, Ndiafhi Daphney; Theron, Annette J.; Tintinger, Gregory Ronald; Steel, Helen C.; Stivaktas, Paraskevi Irene; Richards, Guy A.; Feldman, Charles

doi:10.1093/jac/dkr441

Cited by 12 publications

(11 citation statements)

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“…These properties include the ability to block microglial activation and consequent pro‐inflammatory cytokine release as well as inhibition of matrix metalloproteinases and actions on GABA A and NMDA receptors (Ahmadirad et al., ; Lee et al., ; Wang et al., ; Yan et al., ). Tigecycline, unlike other tetracyclines, has calcium ionophore activity, which could also potentially mediate a suppression of convulsions (Cockeran et al., ).…”

Section: Discussionmentioning

confidence: 99%

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice

Martinez

Groot

Curtis

et al. 2016

Alcoholism Clin & Exp Res

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Background Alcohol Use Disorder (AUD) is a spectrum disorder characterized by mild to severe symptoms, including potential withdrawal signs upon cessation of consumption. Approximately five hundred thousand patients with AUD undergo clinically relevant episodes of withdrawal annually (Kosten and O'Connor, 2003). Recent evidence indicates potential for drugs that alter neuroimmune pathways as new AUD therapies. We have previously shown the immunomodulatory drugs, minocycline and tigecycline, were effective in reducing ethanol consumption in both the two-bottle choice and drinking-in-the-dark paradigms. Here, we test the hypothesis that tigecycline, a tetracycline derivative, will reduce the severity of ethanol withdrawal symptoms in a common acute model of alcohol withdrawal (AWD) using a single anesthetic dose of ethanol in seizure sensitive DBA/2J (DBA) mice. Methods Naive adult female and male DBA mice were given separate injections of 4 g/kg i.p. ethanol with vehicle or tigecycline (0, 20, 40 or 80 mg/kg i.p.). The 80 mg/kg dose was tested at three time-points (0, 4, 7 hrs) post-ethanol treatment. Handling-induced convulsions (HIC) were measured before, and then over 12 hours following ethanol injection. HIC scores and areas under the curve were tabulated. In separate mice, blood ethanol concentrations (BEC) were measured at 2, 4, and 7 hours post injection of 4 g/kg i.p. ethanol in mice treated with 0 and 80 mg/kg i.p. tigecycline. Results AWD symptom onset, peak magnitude, and overall HIC severity were reduced by tigecycline drug treatment compared to controls. Tigecycline treatment was effective regardless of timing throughout AWD, with earlier treatment showing greater efficacy. Tigecycline showed a dose responsive reduction in acute alcohol withdrawal convulsions, with no sex-differences in efficacy. Importantly, tigecycline did not affect BECs over a time course of elimination. Conclusions Tigecycline effectively reduced alcohol withdrawal symptoms in DBA/2J mice at all times and dosages tested, making it a promising lead compound for development of a novel pharmacotherapy for AWD. Further studies are needed to determine the mechanism of tigecycline action.

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Section: Discussionmentioning

confidence: 99%

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice

Martinez

Groot

Curtis

et al. 2016

Alcoholism Clin & Exp Res

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“…Although some studies have demonstrated effective properties of minocycline (second‐generation semisynthetic tetracycline derivative) in the formalin (Cho et al., ) and surgically‐induced neuropathic pain models (Padi and Kulkarni, ), the novel analgesic properties of tetracycline‐like compounds need to be investigated further, especially if tigecycline, or a derivative, is to become an important AUD treatment. In addition to their antimicrobial actions, tetracyclines have been shown to have anti‐inflammatory actions (Cockeran et al., ; Domercq and Matute, ), although these effects have not been investigated for tigecycline. However, the drug is known to have excellent tissue penetration and unappreciable metabolism; unchanged drug is found in the feces, with minor secondary glucuronidation and renal elimination (Meagher et al., ).…”

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confidence: 99%

Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences

Bergeson

Blanton

Martinez

et al. 2016

Alcoholism Clin & Exp Res

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BackgroundPhysicians have long reported that patients with chronic pain show higher tendencies for alcohol use disorder (AUD), and AUD patients appear to have higher pain sensitivities. The goal of this study was to test 2 hypotheses: (i) binge alcohol consumption increases inflammatory pain and mechanical and cold sensitivities; and (ii) tigecycline is an effective treatment for alcohol‐mediated‐increased pain behaviors and sensitivities. Both female and male mice were used to test the additional hypothesis that important sex differences in the ethanol (EtOH)‐related traits would be seen.Methods“Drinking in the Dark” (DID) alcohol consuming and nondrinking control, female and male, adult C57BL/6J mice were evaluated for inflammatory pain behaviors and for the presence of mechanical and cold sensitivities. Inflammatory pain was produced by intraplantar injection of formalin (10 μl, 2.5% in saline). For cold sensation, a 20 μl acetone drop was used. Mechanical withdrawal threshold was measured by an electronic von Frey anesthesiometer. Efficacy of tigecycline (80 mg/kg i.p.) to reduce DID‐related pain responses and sensitivity was tested.Results DID EtOH consumption increased inflammatory pain behavior, while it also produced sustained mechanical and cold sensitivities in both females and males. Tigecycline produced antinociceptive effects in males; a pro‐nociceptive effect was seen in females in the formalin test. Likewise, the drug reduced both mechanical and cold sensitivities in males, but females showed an increase in sensitivity in both tests.ConclusionsOur results demonstrated that binge drinking increases pain, touch, and thermal sensations in both sexes. In addition, we have identified sex‐specific effects of tigecycline on inflammatory pain, as well as mechanical and cold sensitivities. The development of tigecycline as an AUD pharmacotherapy may need consideration of its pro‐nociceptive action in females. Further studies are needed to investigate the mechanism underlying the sex‐specific differences in nociception.

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“…Unlike macrolides that accelerate neutrophil apoptosis and impair neutrophil migration (23), a previous study showed that TGC penetrates neutrophils and maintains their intracellular concentration for a relatively long time. Besides, it enhances the proliferation and proinflammatory activities of neutrophils in vitro (9).…”

Section: White Blood Cell Indicesmentioning

confidence: 99%

“…Previous studies showed harmful effects of TGC on the immune system. It was found to penetrate neutrophils and stimulate their proliferation and cytotoxicity by acting as a calcium ionophore, thus augmenting the innate response (9). However, it could have a suppressive effect on antibodies produced by lymphocytes (10).…”

Section: Immunomodulatory Effects Of Tigecycline In Balb/c Micementioning

confidence: 99%

Immunomodulatory Effects of Tigecycline in Balb/C Mice

Elhayek

Fararjeh²,

Assaf

et al. 2018

Acta Pharmaceutica

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Tigecycline is a glycylcycline antibiotic approved by the FDA for the treatment of complicated infections. Despite its effectiveness, the FDA announced a warning of increasing mortality associated with its use. There is, however, no clear explanation for this side effect. Previous reports found a possible effect of tigecycline on leukocyte proliferation and proinflammatory cytokine release. We t herefore i nvestigated the effect of tigecycline on the immune components and response in Balb/c mice in vivo and in vitro. It was found that tigecycline enhanced lymphocyte proliferation and significantly increased cellular infiltration within the footpad, as based on DTH testing, but reduced the hemagglutination titer. In splenocyte cultures, tigecycline suppressed splenocyte proliferation with IC50 3-5 mmol L-1, significantly increased IL-2 secretion and reduced IL-17 secretion in a dose dependent mode. In conclusion, tigecycline is safe at therapeutic and sub-therapeutic doses, but it could still have an immunomodulatory effect at higher doses. Use of higher doses of tigecycline requires further investigation.

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Calcium-dependent potentiation of the pro-inflammatory functions of human neutrophils by tigecycline in vitro

Abstract: Tigecycline, by functioning as a Ca(2+) ionophore, and independent of antimicrobial activity, potentiates the pro-inflammatory functions of human neutrophils in vitro.

Cited by 12 publications

References 46 publications

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice

Effective Reduction of Acute Ethanol Withdrawal by the Tetracycline Derivative, Tigecycline, in Female and Male DBA/2J Mice

Binge Ethanol Consumption Increases Inflammatory Pain Responses and Mechanical and Cold Sensitivity: Tigecycline Treatment Efficacy Shows Sex Differences

Immunomodulatory Effects of Tigecycline in Balb/C Mice

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