Pyrrolidine dithiocarbamate attenuates the development of acute and chronic inflammation

Abstract

1 The nuclear factor-kB (NF-kB) is a transcription factor which plays a pivotal role in the induction of genes involved in physiological processes as well as in the response to injury and in¯ammation. Dithiocarbamates are antioxidants which are potent inhibitors of NF-kB. 2 We postulated that pyrrolidine dithiocarbamate (PDTC) would attenuate in¯ammation. In the present study we investigate the e ects of PDTC in animal models of acute and chronic in¯ammation (carrageenan-induced pleurisy and collagen-induced arthritis). 3 We report here for the ®rst time that PDTC (given at 100, 30 or 10 mg kg 71 i.p. in the pleurisy model or at 10 mg kg 71 i.p. every 48 h in the arthritis model) exerts potent anti-in¯ammatory e ects (e.g. signi®cant reduction of (A) pleural exudate formation, (B) polymorphonuclear cell in®ltration, (C) lipid peroxidation, (D) inducible nitric oxide synthase (iNOS) activity and nitric oxide production (E) plasma and pleural exudates levels of interleukin-1b and tumour necrosis factor-a, (F) histological injury and (G) delayed development of clinical indicators). 4 Furthermore, PDTC reduced immunohistochemical evidence of (A) formation of nitrotyrosine, (B) activation of poly (ADP-ribose) polymerase (PARP), (C) expression of iNOS and (D) expression of cyclo-oxygenase-2 (COX-2) in the lungs of carrageenan-treated mice and in the joints from collagen-treated mice. 5 Additionally, Western blotting and immunohistochemical analysis of lung tissue revealed that PDTC prevented degradation of IKB-a and translocation of NF-kB from the cytoplasm into the nucleus. 6 Taken together, our results clearly demonstrate that prevention of the activation of NF-kB by PDTC reduces the development of acute and chronic in¯ammation. Therefore, inhibition of NF-kB may represent a novel approach for the therapy of in¯ammation.

Pyrrolidine dithiocarbamates of Pd(II)

“…The complex [PtCl(ESDT)(Py)] showed cytotoxic efficacy, the ability to overcome cisplatin resistance and low nephrotoxicity in respect to cisplatin [16,17], whereas the palladium analoge causes severe damages in the kidney [18]. The dithiocarbamates examined (essentially ESDT, Me 2 DT or Et 2 DT) do not present particular properties by themselves, apart from the general detoxicant ability, whereas pyrrolidine dithiocarbamate has been widely reported in the last three years owing to antioxidant, antiviral and antiinflammatory properties and metal transport in membranes [19][20][21][22][23][24]. We thought then, of interest to extend the study to such a particular dithiocarbamate.…”

Formation of Highly Reactive A-ring and J-ring Isoprostane-like Compounds (A4/J4-neuroprostanes) in Vivo from Docosahexaenoic Acid

“…Cyclopentenone PGs have attracted considerable interest because of their ability to modulate cell proliferation and differentiation. For example, various compounds of the A-and J-series have been shown to inhibit proliferation with a G 1 cell cycle arrest and to induce differentiation (13)(14)(15). The concentrations of compounds required for this activity are frequently in the micromolar range or above.…”

Antioxidant Therapy as a Potential Approach to Severe Influenza-Associated Complications

“…The findings support the notion that an agent with antiviral and antioxidant activities can be a drug of choice for the treatment of patients with severe influenza-associated complications and that PDTC could be one of these drug candidates. Since PDTC is well tolerated in vivo at doses of up to 100 mg/kg (intraperitoneal injection) and exhibits therapeutic effects on animal inflammation and tissue injury models [35][36][37][38], further studies on the therapeutic effect of PDTC on animal influenza models are warranted. complexes, and rapid transport via a lipophilic complex by PDTC has been proposed to explain the intracellular recruitment of copper and zinc ions from the extracellular medium [39].…”