Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

Liby, Karen T.; Sporn, Michael B.

doi:10.1124/pr.111.004846

Cited by 358 publications

(343 citation statements)

References 287 publications

(406 reference statements)

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“…The oleanolic acid synthetic derivative, bardoxolone methyl (BM) has attracted attention due to its potential application in a wide variety of diseases , Liby and Sporn, 2012, Reisman et al , 2012. A recent study found that BM can promote dopaminergic neuroprotection via attenuation of the inflammatory mediator, tumour necrosis factor alpha (TNFα), and reactive oxygen species (ROS) production in vitro (Tran et al , 2008).…”

Section: Introductionmentioning

confidence: 99%

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

Camer

Szabo

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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X. (2015). Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 59 68-75. Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory AbstractHigh fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood-brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), a HF (40% of energy as fat), or a HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. Recognition memory was assessed by performing a novel object recognition test on the treated mice. Downstream brain-derived neurotrophic factor (BDNF) signalling molecules were examined in the prefrontal cortex (PFC) and hippocampus of mice via Western blotting and N-methyl-d-aspartate (NMDA) receptor binding. BM treatment prevented HF dietinduced impairment in recognition memory (p < 0.001). In HF diet fed mice, BM administration attenuated alterations in the NMDA receptor binding density in the PFC (p < 0.05), however, no changes were seen in the hippocampus (p > 0.05). In the PFC and hippocampus of the HF diet fed mice, BM administration improved downstream BDNF signalling as indicated by increased protein levels of BDNF, phosphorylated tropomyosin related kinase B (pTrkB) and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p < 0.05). BM administration also prevented the HF diet-induced increase in the protein levels of inflammatory molecules, phosphorylated c-Jun N-terminal kinase (pJNK) in the PFC, and protein tyrosine phosphatase 1B (PTP1B) in both the PFC and hippocampus. In summary, these findings suggest that BM prevents HF diet-induced impairments in recognition memory by improving downstream BDNF signal transduction, increasing pAMPK, and reducing inflammation in the PFC and hippocampus. AbstractHigh-fat (HF) diets are known to induce changes in synaptic plasticity in the forebrain leading to learning and memory impairments. Previous studies of oleanolic acid derivatives have found that these compounds can cross the blood brain barrier to prevent neuronal cell death. We examined the hypothesis that the oleanolic acid derivative, bardoxolone methyl (BM) would prevent diet-induced cognitive deficits in mice fed a HF diet. C57BL/6J male mice were fed a lab chow (LC) (5% of energy as fat), HF (40% of energy as fat), or HF diet supplemented with 10 mg/kg/day BM orally for 21 weeks. and phosphorylated protein kinase B (pAkt), and increased phosphorylated AMP-activated protein kinase (pAMPK) (p<0.05). BM a...

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Section: Introductionmentioning

confidence: 99%

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

Camer

Szabo

et al. 2015

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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“…The synthetic oleanane triterpenoid 2-cyano-3,12-dioxo olean-1,9-dien-28-olic acid (CDDO) and its derivatives are small molecules with potent antiinflammatory and anticarcinogenic properties (22)(23)(24)(25)(26)(27)(28)(29). The synthetic triterpenoids inhibit expression of inflammatory mediators, such as inducible NOS (iNOS) and inducible cyclooxygenase-2 (COX-2), through suppression of various inflammatory cytokines, such as IFN-γ, IL-1β, and TNF-α (30,31), and also by direct inhibition of the signaling intermediate STAT3 (32).…”

Section: Introductionmentioning

confidence: 99%

Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

Choi¹,

Kim²,

Robinson³

et al. 2014

J. Clin. Invest.

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Colitis-associated colon cancer (CAC) develops as a result of inflammation-induced epithelial transformation, which occurs in response to inflammatory cytokine-dependent downregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and subsequent suppression of prostaglandin metabolism. Agents that both enhance 15-PGDH expression and suppress cyclooxygenase-2 (COX-2) production may more effectively prevent CAC. Synthetic triterpenoids are a class of small molecules that suppress COX-2 as well as inflammatory cytokine signaling. Here, we found that administration of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9 (11)

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“…One potent synthetic derivative of oleanolic acid, capable of strongly activating Nrf2, is 2‐cyano‐3,12‐dioxo‐oleana‐1,9,‐dien‐28‐oic acid (CDDO), also known as bardoxolone methyl (BM) or RTA 401 53. Subsequent chemical modifications of CDDO led to the development of the triterpenoid, dihydro‐CDDO‐trifluoroethyl amide (dh404).…”

Section: Diabetes and Cardiovascular Diseasementioning

confidence: 99%

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

et al. 2018

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Diabetes is considered a major burden on the healthcare system of Western and non‐Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro‐ and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism‐based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu.

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Synthetic Oleanane Triterpenoids: Multifunctional Drugs with a Broad Range of Applications for Prevention and Treatment of Chronic Disease

Cited by 358 publications

References 287 publications

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

Bardoxolone methyl prevents high-fat diet-induced alterations in prefrontal cortex signalling molecules involved in recognition memory

Synthetic triterpenoid induces 15-PGDH expression and suppresses inflammation-driven colon carcinogenesis

Recent novel approaches to limit oxidative stress and inflammation in diabetic complications

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