In silico identification and in vivo characterization of small molecule therapeutic hypothermia mimetics

Coderch, Claire; Cerio, María Díaz de; Zapico, José María; Peláez, Rafael Pila; Larráyoz, Ignacio M.; Ramos, Ana; Martı́nez, Alfredo; Pascual‐Teresa, Beatriz de

doi:10.1016/j.bmc.2017.10.039

Cited by 12 publications

(24 citation statements)

References 41 publications

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“…There are several promising therapies to target CIRBP in vivo . Coderch et al (2017) identified the first small-molecule CIRBP inducers. A single IP bolus of compound Zr17-2 (∼6.5 μg/kg) increased CIRBP levels in the lung and in the pancreas 4 days later in normothermic rats and CIRBP levels modestly increased in the cerebral cortex.…”

Section: Induction Of Csps During Cold Stress: Potential Applicationsmentioning

confidence: 99%

A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis

Jackson

Kochanek

2019

Therapeutic Hypothermia and Temperature Management

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Three decades of animal studies have reproducibly shown that hypothermia is profoundly cerebroprotective during or after a central nervous system (CNS) insult. The success of hypothermia in preclinical acute brain injury has not only fostered continued interest in research on the classic secondary injury mechanisms that are prevented or blunted by hypothermia but has also sparked a surge of new interest in elucidating beneficial signaling molecules that are increased by cooling. Ironically, while research into cold-induced neuroprotection is enjoying newfound interest in chronic neurodegenerative disease, conversely, the scope of the utility of therapeutic hypothermia (TH) across the field of acute brain injury is somewhat controversial and remains to be fully defined. This has led to the era of Targeted Temperature Management, which emphasizes a wider range of temperatures (33–36°C) showing benefit in acute brain injury. In this comprehensive review, we focus on our current understandings of the novel neuroprotective mechanisms activated by TH, and discuss the critical importance of developmental age germane to its clinical efficacy. We review emerging data on four cold stress hormones and three cold shock proteins that have generated new interest in hypothermia in the field of CNS injury, to create a framework for new frontiers in TH research. We make the case that further elucidation of novel cold responsive pathways might lead to major breakthroughs in the treatment of acute brain injury, chronic neurological diseases, and have broad potential implications for medicines of the distant future, including scenarios such as the prevention of adverse effects of long-duration spaceflight, among others. Finally, we introduce several new phrases that readily summarize the essence of the major concepts outlined by this review—namely, Ultramild Hypothermia, the “Responsivity of Cold Stress Pathways,” and “Hypothermia in a Syringe.”

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Section: Induction Of Csps During Cold Stress: Potential Applicationsmentioning

confidence: 99%

A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis

Jackson

Kochanek

2019

Therapeutic Hypothermia and Temperature Management

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“…Such a compound could serve to treat acute brain injury and chronic disease. A preliminary successful example has already been developed with the CIRP homologue, although its activity requires further tests 42 . In addition, the safety of RBM3-based therapy will need to be carefully evaluated for potential tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

RBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury

et al. 2019

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Hypoxic ischemia (HI) is an acute brain threat across all age groups. Therapeutic hypothermia ameliorates resulting injury in neonates but its side effects prevent routine use in adults. Hypothermia up-regulates a small protein subset that includes RNA-binding motif protein 3 (RBM3), which is neuroprotective under stressful conditions. Here we show how RBM3 stimulates neuronal differentiation and inhibits HI-induced apoptosis in the two areas of persistent adult neurogenesis, the subventricular zone (SVZ) and the subgranular zone (SGZ), while promoting neural stem/progenitor cell (NSPC) proliferation after HI injury only in the SGZ. RBM3 interacts with IGF2 mRNA binding protein 2 (IMP2), elevates its expression and thereby stimulates IGF2 release in SGZ but not SVZ-NSPCs. In summary, we describe niche-dependent regulation of neurogenesis after adult HI injury via the novel RBM3-IMP2-IGF2 signaling pathway.

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“…Zr17‐2 was a first synthesized CIRBP agonist which was reported to be capable of modulating the activity of CIRBP even in the absence of a cold stimulus 8 . It is a small molecule that interacts simultaneously with the flexible part of CIRBP and the RNA‐binding site to inhibit degradation of CIRBP by protease, thus maintaining its active form.…”

Section: Discussionmentioning

confidence: 99%

“…Zr17-2 was a first synthesized CIRBP agonist which was reported to be capable of modulating the activity of CIRBP even in the absence of a cold stimulus. 8 It is a small molecule that interacts simultaneously with the flexible part of CIRBP and the RNA-binding site to inhibit degradation of CIRBP by protease, thus maintaining its active form. In this study, we found Zr17-2-blocked CIRBP degradation in cardiomyocytes to preserve the active protein and its functions for longer periods of time, thereby enhancing CoQ 10 biosynthesis to protect cardiomyocytes against oxidative stress and promote ATP production during extended heart preservation.…”

Section: E417mentioning

confidence: 99%

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Cold‐inducible RNA binding protein agonist enhances the cardioprotective effect of UW solution during extended heart preservation

et al. 2020

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In heart transplantation, time restriction is an unavoidable thorny problem during cardiac transport. Cold storage is an important organ preservation method in donor heart transport. Cold‐inducible RNA binding protein (CIRBP) has been proven to play a protective role under cold stress. In this study, we investigated the role of CIRBP in hypothermic cardioprotection during heart preservation in UW solution and explored a new approach to extend the heart preservation time. Cirbp‐knockout (Cirbp−/−), Cirbp‐transgenic (Cirbp‐Tg), and wild‐type rats were, respectively, randomized into two groups based on various heart preservation times (6 or 12‐hour group) (n = 8 per group). After preservation in UW solution, all hearts were mounted on a Langendorff apparatus and underwent measurement of cardiac parameters, histological analysis, and molecular study. Within the 6‐hour preservation group, no significant difference was found in cardiac functions and histological changes between different rat species. However, after 12 hours of preservation, Cirbp−/− rat hearts showed more apoptosis and worse cardiac function, but less apoptosis and better cardiac function were observed in Cirbp‐Tg rat hearts. Furthermore, we found CIRBP‐mediated cardiac ubiquinone (CoQ10) biosynthesis plays an important role in extending heart preservation, and ubiquinone biosynthesis protein COQ9 was an essential down‐stream regulator during this process. Finally, we found that zr17‐2, a CIRBP agonist, could enhance the expression of CIRBP, which further enhances the synthesis of CoQ10 and promotes scavenging of reactive oxygen species and ATP production to extend heart preservation. This study demonstrated that CIRBP‐enhanced CoQ10 biosynthesis during hypothermic heart preservation and zr17‐2‐supplemented UW solution could be a promising approach to ameliorate heart damage and extend heart preservation during cardiac transport.

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In silico identification and in vivo characterization of small molecule therapeutic hypothermia mimetics

Cited by 12 publications

References 41 publications

A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis

A New Vision for Therapeutic Hypothermia in the Era of Targeted Temperature Management: A Speculative Synthesis

RBM3 promotes neurogenesis in a niche-dependent manner via IMP2-IGF2 signaling pathway after hypoxic-ischemic brain injury

Cold‐inducible RNA binding protein agonist enhances the cardioprotective effect of UW solution during extended heart preservation

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