Effects of Lazaroids on Intestinal Ischemia and Reperfusion Injury in Experimental Models

Δ9,11 modifications of glucocorticoids (21-aminosteroids) have been developed as drugs for protection against cell damage (lipid peroxidation; lazaroids) and inhibition of neovascularization (anecortave). Part of the rationale for developing these compounds has been the loss of glucocorticoid receptor binding due to the Δ9,11 modification, thus avoiding many immunosuppressive activities and deleterious side effect profiles associated with binding to glucocorticoid and mineralocorticoid receptors. We recently demonstrated that anecortave acetate and its 21-hydroxy analog (VBP1) do, in fact, show glucocorticoid and mineralocorticoid receptor binding activities, with potent translocation of the glucocorticoid receptor to the cell nucleus. We concluded that Δ9,11 steroids showed novel anti-inflammatory properties, retaining NF-κB inhibition, but losing deleterious glucocorticoid side effect profiles. Evidence for this was developed in pre-clinical trials of chronic muscle inflammation. Here, we describe a drug development program aimed at optimizing the Δ9,11 chemistry. Twenty Δ9,11 derivatives were tested in in vitro screens for NF-κB inhibition and GR translocation to the nucleus, and low cell toxicity. VBP15 was selected as the lead compound due to potent NF-κB inhibition and GR translocation similar to prednisone and dexamethasone, lack of transactivation properties, and good bioavailability. Phamacokinetics were similar to traditional glucocorticoid drugs with terminal half-life of 0.35 h (mice), 0.58 h (rats), 5.42 h (dogs), and bioavailability of 74.5% (mice), and 53.2% (dogs). Metabolic stability showed ≥80% remaining at 1 h of VBP6 and VBP15 in human, dog, and monkey liver microsomes. Solubility, permeability and plasma protein binding were within acceptable limits. VBP15 moderately induced CYP3A4 across the three human hepatocyte donors (24–42%), similar to other steroids. VBP15 is currently under development for treatment of Duchenne muscular dystrophy.

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“…Pre-clinical work in additional indications continues, including multiple wound states and lung disease. 7–9 …”

Section: Introductionmentioning

confidence: 99%

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

Reeves

Hoffman

Nagaraju

et al. 2013

Bioorganic & Medicinal Chemistry

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“…Heat stress can cause excessive reactive oxygen species, which can attack intestinal epithelial cells to induce damage, dysfunction and apoptosis (Flessas, Papalois, Toutouzas, Zagouri, & Zografos, ; Gu et al., ). In the present study, the addition of CT increased antioxidant enzyme activity and reduced MDA concentration in the jejunum of heat‐stressed broilers.…”

Section: Discussionmentioning

confidence: 99%

Effects of chestnut tannins on intestinal morphology, barrier function, pro‐inflammatory cytokine expression, microflora and antioxidant capacity in heat‐stressed broilers

Liu

Zhao

et al. 2017

Animal Physiology Nutrition

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A study was conducted to evaluate the effects of chestnut tannins (CT) on intestinal morphology, barrier function, pro-inflammatory cytokine expression, microflora and antioxidant capacity in heat-stressed broilers. Four hundred 28-day-old male Ross 308 broilers were randomly assigned into four groups, with 10 replicates per group and 10 broilers per replicate. The broilers in the normal (NOR) group were kept at 22 ± 1°C and fed the basal diet, and each of the other three groups were treated with cyclic heat (33 ± 1°C from 0800 to 1800 and 22 ± 1°C from 1800 to 0800) and fed the basal diet with 0 (HT), 1 (CT1) or 2 (CT2) g of CT/kg of diet. The experiment lasted for 14 days. Compared with the HT group, broilers in the NOR and CT2 groups had higher (p < .05) average daily gain and villus height in the jejunum and lower serum d-lactate (p < .001) and diamine oxidase (p < .01) levels. The addition of 2 g CT/kg of diet increased the total antioxidant capacity (p < .001) and superoxide dismutase activities (p < .05) and zonula occludens-1 mRNA expression level (p < .05) and decreased the malondialdehyde concentration (p < .01) and mRNA expression levels of interleukin-6 (p < .001) and nuclear factor kappa B (p < .001) in the jejunal mucosa of heat-stressed broilers. The populations of Escherichia coli and Clostridium in the jejunum (p < .01) and caecum (p < .05) of broilers in the HT group were higher than those in the NOR and CT2 groups. In conclusion, the addition of 2 g CT/kg of diet seemed to be a feasible means of alleviating the negative effects of heat stress on the growth performance and intestinal function of broilers.

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“…Furthermore, we found that the underlying mechanisms of action of osthole in preventing intestinal I/R injury involved the inhibition of NF-κB. The production of free radicals from oxygen molecules derived from the electron transport chains of mitochondrial cells, endothelial cells and activated neutrophils elicits oxidative stress and enhances intestinal I/R injury (33). Thus, the antioxidant, SOD, is considered to play a crucial role in relieving oxidative stress during I/R injury.…”

Section: Discussionmentioning

confidence: 96%

Protective effects of osthole, a natural derivative of coumarin, against intestinal ischemia-reperfusion injury in mice

Dong

Zhang

Liu

et al. 2013

International Journal of Molecular Medicine

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Intestinal ischemia/reperfusion (I/R) injury is considered to be associated with high morbidity and mortality rates. Osthole, a natural derivative of coumarin, has been shown to exert a variety of pharmacological and therapeutic effects under physiological and pathological conditions. In the present study, to investigate the protective effects of osthole against intestinal I/R injury, various doses of osthole (5, 10, 25 and 50 mg/kg) were pre-administered to mice subjected to intestinal I/R injury. A dose-dependent increase in the survival rate was observed in the osthole-treated mice. Pre-treatment with osthole (50 mg/kg) attenuated the destruction of epithelial cells within the villi induced by intestinal I/R injury, and suppressed oxidative stress, neutrophil infiltration and modulated nitric oxide (NO) levels. Moreover, the increased IκBα phosphorylation and nuclear factor (NF)-κB nuclear translocation induced by I/R injury were significantly decreased following pre-treatment with osthole. Taken together, our data demonstrate that osthole exerts protective effects against intestinal I/R injury in mice by suppressing oxidative stress, neutrophil infiltration and NO levels, partly through the inhibition of NF-κB nuclear translocation. Hence, the findings of the present study provide insight into the mechanisms through which osthole exerts its protective effects against intestinal I/R injury.

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Effects of Lazaroids on Intestinal Ischemia and Reperfusion Injury in Experimental Models

Cited by 27 publications

References 35 publications

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

VBP15: Preclinical characterization of a novel anti-inflammatory delta 9,11 steroid

Effects of chestnut tannins on intestinal morphology, barrier function, pro‐inflammatory cytokine expression, microflora and antioxidant capacity in heat‐stressed broilers

Protective effects of osthole, a natural derivative of coumarin, against intestinal ischemia-reperfusion injury in mice

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