Anti-inflammatory properties of new adamantane derivatives. Design, synthesis, and biological evaluation

A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti-inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker’s yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs)

Anti-inflammatory properties of new adamantane derivatives. Design, synthesis, and biological evaluation

A series of adamantane-containing molecules consisting of two lipophilic centers which are linked by different bridges (oxime esters, oxime ethers, amides, and symmetric alcohols), were designed and synthesized as anti- inflammatory agents. Their anti-inflammatory activity was evaluated as their ability to inhibit phlogistic-induced mouse paw edema. Some of the tested compounds exhibited activity comparable to that of diclofenac, others had a weaker activity, while some oxime esters proved to enhance the inflammatory response. In all cases, activity was dose-dependent. The deacylated compound 10 was found to be the most active of the series, inhibiting inflammation due to Baker's yeast, the mechanism of which involves mainly the activation of lipoxygenase and/or complement systems, a property which is absent from most selective cyclooxygenase only inhibiting non-steroidal anti-inflammatory drugs (NSAIDs)

Effects of the novel non-steroidal anti-inflammatory compound N-(2-thiolethyl)-2-2-[N’-2,6-dichlorophenyl amino]phenylacetamide on cytokines and apoptosis in ischaemic rat brain

Ischaemia-reperfusion injury is associated with an inflammatory response as well as apoptosis in the affected area. Inflammatory responses are characterized, among others, by an increased production of several cytokines, while caspases are implicated in the control of apoptosis. The aim of the present work was to determine changes in the levels of inflammatory and apoptotic indices in the rat brain after cerebral ischaemia-reperfusion and to evaluate the effect of the non-steroidal anti-inflammatory compound N-(2-thiolethyl)-2-2-[N’-[2,6-dichlorophenyl)amino]phenyl acetamide on these indices. A cerebral ischaemia-reperfusion rodent model was used to investigate, via immunohistochemical and colorimetric techniques, the presence in the brain and spleen of inflammatory enzymes cycloxygenases COX-1 and COX-2, cytokines interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-18, tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) as well as the activated form of caspase-3, in treated and untreated animals. Cerebral ischaemia-reperfusion caused elevated levels in the rat brain of all enzymes and cytokines included in this study, at 1, 3 and 5 days post ischaemia. Treatment with the anti-inflammatory derivative reduced the elevation, caused by ischaemia, of IFN-γ, TNF-α, IL-1β IL-6, IL-18 and caspase-3 levels at 3 days post ischaemia, while it increased the levels of IL-10. It was shown that the increase in concentrations of a wide range of cytokines involved in the inflammatory reaction causing brain damage after ischaemia-reperfusion can be partially reversed by the anti-inflammatory derivative used in this study. © ECV · Editio Cantor Verlag

α1Acid glycoprotein production in rat dorsal air pouch in response to inflammatory stimuli, dexamethasone and honey bee venom

This study shows the rapid and differential production of the 40–43 kDa and the 70–90 kDa α1-acid glycoprotein (AGP) fucosylated glycoforms after treatment of the dorsal air pouch with bacterial lipopolysaccharide (LPS), HgCl(2) or Freund's complete adjuvant (FCA). The 40–43 kDa and the 70–90 kDa AGP production is peaked 1–3 h post-LPS treatment. We observed that the responses to LPS and FCA are similar in that both AGP isoforms are induced whereas they differ in that the FCA exhibits a 6 h lag period. The response to HgCl(2,) however, exhibits the specific biphasic induction only of the 40–43 kDa AGP. The serum 40–43 kDa AGP glycoform gradually increases in response to all of the above stimulants and peaks by 24 h post- treatment. The increase of the 70–90 kDa AGP levels in the air pouch occurs in association with the accumulation of polymorphonuclear (PMN) cells while dexamethasone (DEX) increases only the 40–43 kDa AGP production in the absence of PMN accumulation. Macrophage–monocyte lineage cells forming the air pouch lining tissue may potentially be the cells that secrete the 40–43 kDa AGP while polymorphonuclear cells that infiltrate the air pouch secrete the 70–90 kDa AGP. The 40–43 kDa and 70–90 kDa AGP production induced by LPS in the air pouch precedes that of interleukin-1 (IL-1) or interleukin-6 (IL-6) while the 40–43 kDa AGP glycoform potentially increases IL-6 production by air pouch PMN exudate cells. These significant differences suggest a local pro-inflammatory role of AGP. Honeybee venom suppressed arthritis development and exhibited differential local or systemic regulation of AGP in serum vs. air pouch exudate or synovial fluid. This study with the air pouch model of facsimile synovium tissue suggests that local α1-acid glycoprotein (AGP) production may contribute to pro-inflammatory and anti-inflammatory activities during the local acute phase response or during chronic inflammatory stress as in arthritis

α1-Acid glycoprotein production in rat dorsal air pouch in response to inflammatory stimuli, dexamethasone and honey bee venom

This study shows the rapid and differential production of the 40-43 kDa and the 70-90 kDa α1-acid glycoprotein (AGP) fucosylated glycoforms after treatment of the dorsal air pouch with bacterial lipopolysaccharide (LPS), HgCl2 or Freund's complete adjuvant (FCA). The 40-43 kDa and the 70-90 kDa AGP production is peaked 1-3 h post-LPS treatment. We observed that the responses to LPS and FCA are similar in that both AGP isoforms are induced whereas they differ in that the FCA exhibits a 6 h lag period. The response to HgCl2, however, exhibits the specific biphasic induction only of the 40-43 kDa AGP. The serum 40-43 kDa AGP glycoform gradually increases in response to all of the above stimulants and peaks by 24 h post- treatment. The increase of the 70-90 kDa AGP levels in the air pouch occurs in association with the accumulation of polymorphonuclear (PMN) cells while dexamethasone (DEX) increases only the 40-43 kDa AGP production in the absence of PMN accumulation. Macrophage-monocyte lineage cells forming the air pouch lining tissue may potentially be the cells that secrete the 40-43 kDa AGP while polymorphonuclear cells that infiltrate the air pouch secrete the 70-90 kDa AGP. The 40-43 kDa and 70-90 kDa AGP production induced by LPS in the air pouch precedes that of interleukin-1 (IL-1) or interleukin-6 (IL-6) while the 40-43 kDa AGP glycoform potentially increases IL-6 production by air pouch PMN exudate cells. These significant differences suggest a local pro-inflammatory role of AGP. Honeybee venom suppressed arthritis development and exhibited differential local or systemic regulation of AGP in serum vs. air pouch exudate or synovial fluid. This study with the air pouch model of facsimile synovium tissue suggests that local α1-acid glycoprotein (AGP) production may contribute to pro-inflammatory and anti-inflammatory activities during the local acute phase response or during chronic inflammatory stress as in arthritis. © 2010 Elsevier Inc