Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice

Park, Sung Bum; Jung, Won Hoon; Kang, Nam Sook; Park, Ji Seon; Bae, Gyu Hwan; Kim, Hee Youn; Rhee, Sang Dal; Kang, Seung Kyu; Ahn, Jin Hee; Jeong, Hye Gwang; Kim, Ki Young

doi:10.1016/j.ejphar.2013.09.052

Cited by 13 publications

(9 citation statements)

References 41 publications

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“…Numerous lines of evidence in models of diabetes, cardiovascular dysfunction, and obesity confirm the role of p38 as a possible mediator of IGFs/insulin resistance induced by oxidative stress (37)(38)(39)(40)(41)(42) and the potential benefits of its inhibition (43,44). p38 redox activation prevents IRS-1/2 phosphorylation by IGF-I or insulin, blocking in this way PI3K and AKT activation (45).…”

Section: Discussionmentioning

confidence: 99%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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Disruption of insulin-like growth factor I (IGF-I) signaling is a key step in the development of cancer or neurodegeneration. For example, interference of the prosurvival IGF-I/AKT/ FOXO3 pathway by redox activation of the stress kinases p38 and JNK is instrumental in neuronal death by oxidative stress. However, in astrocytes, IGF-I retains its protective action against oxidative stress. The molecular mechanisms underlying this cell-specific protection remain obscure but may be relevant to unveil new ways to combat IGF-I/insulin resistance. Here, we describe that, in astrocytes exposed to oxidative stress by hydrogen peroxide (H 2 O 2 ), p38 activation did not inhibit AKT (protein kinase B) activation by IGF-I, which is in contrast to our previous observations in neurons. Rather, stimulation of AKT by IGF-I was significantly higher and more sustained in astrocytes than in neurons either under normal or oxidative conditions. This may be explained by phosphorylation of the phosphatase PTEN at the plasma membrane in response to IGF-I, inducing its cytosolic translocation and preserving in this way AKT activity. Stimulation of AKT by IGF-I, mimicked also by a constitutively active AKT mutant, reduced oxidative stress levels and cell death in H 2 O 2 -exposed astrocytes, boosting their neuroprotective action in co-cultured neurons. These results indicate that armoring of AKT activation by IGF-I is crucial to preserve its cytoprotective effect in astrocytes and may form part of the brain defense mechanism against oxidative stress injury. IGF-I2 is a pleiotropic growth factor with important prosurvival effects in neurons (1). One of the main downstream targets of IGF-I is the Ser/Thr kinase AKT (2), which mediates cell survival and proliferation (3). Upon its activation, the IGF-I receptor recruits and phosphorylates IRS docking proteins (4), which allows translocation of phosphatidylinositol 3-kinase (PI3K) to the plasma membrane where it catalyzes the formation of the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP 3 ) (5). AKT is recruited to the membrane by interaction with these messengers so that it can be fully activated by PDK1 and mTORC2 kinases (3,6). This pathway is switched off (to prevent uncontrolled proliferation) through activation of the lipid and protein phosphatase PTEN, which catalyzes PIP 3 dephosphorylation (4).Cell metabolism generates potentially harmful reactive oxygen species (ROS), which at moderate levels can act as second messengers (7). However, chronic and/or abrupt increases of ROS (uncontainable by detoxification through cellular defenses) generates oxidative stress, a pathological cellular condition that can interfere with redox-sensitive signaling pathways (7). Neurons are particularly vulnerable to oxidative stress because of their low ROS detoxifying capacity (8).We previously described that oxidative stress interferes with the IGF-I/PI3K/AKT pathway by redox activation of p38 kinase to induce neuronal death (9). IGF-I signaling impairment by oxidative stress ha...

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Section: Discussionmentioning

confidence: 99%

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Dávila

Fernández

Torres‐Alemán

2016

Journal of Biological Chemistry

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“…Thus, several adamantyl-containing 11β-HSD1 inhibitors exhibit high affinity and potency and some of them (e.g. AZD8329 and ABT-384) have reached clinical trials ( Figure 1) [26][27][28][29][30][31][32][33][34]. Although the evaluation of alternative polycyclic hydrocarbons may offer further opportunities for optimizing the space filling of the hydrophobic cavity, the use of other polycyclic substituents featuring different size or shape has only been briefly scrutinized (e.g.…”

Section: Design Synthesis and In Vitro Evaluation Of New Inhibitorsmentioning

confidence: 99%

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Leiva

Griñán-Ferré

Seira

et al. 2017

European Journal of Medicinal Chemistry

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Recent findings suggest that treatment with 11β-HSD1 inhibitors provides a novel approach to deal with age-related cognitive dysfunctions, including Alzheimer's disease. In this work we report potent 11β-HSD1 inhibitors featuring unexplored pyrrolidine-based polycyclic substituents. A selected candidate administered to 12-month-old SAMP8 mice for four weeks prevented memory deficits and displayed a neuroprotective action. This is the first time that 11β-HSD1 inhibitors have been studied in this broadly-used mouse model of accelerated senescence and late-onset Alzheimer's disease.

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“…Compound KR-67105 also led to a concentration-dependent 11β-HSD1 inhibition [29]. In non-obese C57BL/6 mice the treatment with 60 mg/Kg originated the maximum inhibition in liver (between 65-70%), followed by the treatment with 40 mg/Kg, with inhibition below 50%.…”

Section: In Vivo Preclinical Trialsmentioning

confidence: 90%

“…In this case, the results suggested that this experimental drug may improve glucose tolerance and insulin sensitivity by inhibiting 11β-HSD1 activity. Besides, KR-67105 also shows anti-diabetic action by the suppression of diabetes related gene expressions such as G6Pase and PEPCK in the liver after 100 mg/kg administration to DIO-C57BL/6 mice [29].…”

Section: In Vivo Preclinical Trialsmentioning

confidence: 99%

Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 as Potential Drugs for Type 2 Diabetes Mellitus—A Systematic Review of Clinical and In Vivo Preclinical Studies

2021

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Diabetes mellitus is a pathology with increasing frequency in society, being one of the main causes of death worldwide. For this reason, new therapeutic targets have been studied over the years. 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme responsible for reducing cortisone to its active form cortisol, which can lead to metabolic changes such as insulin resistance and hyperglycemia. Therefore, 11β-HSD1 inhibition may offer a new therapeutic approach for type 2 diabetes mellitus. This work intends to systematically review the available scientific evidence on this subject. For this, a search was conducted in three databases and 15 clinical and in vivo preclinical studies were included in this review. Despite the high inhibitory and selectivity levels achieved with several molecules and the demonstrated clinical efficacy in diabetes treatment, no phase III clinical trials have yet been conducted. This is important because the long-term effects of 11β-HSD1 inhibitors including the consequences in hypothalamic–pituitary–adrenal axis must be evaluated. However, this enzyme remains a promising target for drug development, including due to its effectiveness in controlling various factors that constitute the metabolic syndrome and its potential for multiple indications in patients with diabetes, including wound healing and weight loss.

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Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice

Cited by 13 publications

References 41 publications

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Astrocyte Resilience to Oxidative Stress Induced by Insulin-like Growth Factor I (IGF-I) Involves Preserved AKT (Protein Kinase B) Activity

Design, synthesis and in vivo study of novel pyrrolidine-based 11β-HSD1 inhibitors for age-related cognitive dysfunction

Inhibitors of 11β-Hydroxysteroid Dehydrogenase Type 1 as Potential Drugs for Type 2 Diabetes Mellitus—A Systematic Review of Clinical and In Vivo Preclinical Studies

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