Prolyl hydroxylase domain inhibitors: can multiple mechanisms be an opportunity for ischemic stroke?

Lanigan, Sinead M.; O’Connor, John

doi:10.1016/j.neuropharm.2018.12.021

Cited by 19 publications

(10 citation statements)

References 145 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Hypoxia-inducible factor (HIF) has critical functions in modulating orchestrated transcriptional programs in angiogenesis, metabolism, and erythropoiesis . These programs are generally related to human diseases including anemia, ischemia stroke, neurodegenerative diseases, and acute kidney injury (AKI), , making HIF a promising therapeutic target. The current standard treatment for ischemic diseases is by restoring sufficient red blood cell (RBC) production through intravenous or subcutaneous administration of recombinant human erythropoietin (rhEPO) and its analogues .…”

Section: Introductionmentioning

confidence: 99%

“…It has been demonstrated that PHD2 inhibitors could stabilize HIF pathway and increase EPO, HO-1, and VEGF expression in kidney, brain, and other tissues. Thus, it may be of benefit for the development of new therapies for ischemic diseases, kidney diseases, and neurodegenerative diseases. , However, most PHD2 inhibitors lack tissue selectivity and have wide-spectrum HIF activating capacity in vivo; this might cause undesirable effects because of the complication of the genes targeted by the HIF pathway. Systemic PHD inhibition may cause pleiotropic effects. , With the purpose of alleviating the potential risk of unfavorable systemic effects, a photoactivatable PHD2 inhibitor was designed that may offer promising potentials for the tissue-specific therapies for HIF-related diseases with the combination of light irradiation onto target tissues.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light

Jiang

et al. 2019

J. Med. Chem.

View full text Add to dashboard Cite

HIF prolyl hydroxylase 2 (PHD2) inhibitors represent a novel approach for treating HIF-related diseases. This study reports the first application of photoremovable protecting group to the photoactivatable inhibitor (7) of PHD2. It allows the inhibitory activity for PHD2 to be controlled by light irradiation, subsequently stabilizing HIF and promoting expression of the target gene. Light activation to stabilize HIF offers promising potentials for the tissue-specific therapies for HIF-related disease by light irradiation onto target tissues.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light

Jiang

et al. 2019

J. Med. Chem.

View full text Add to dashboard Cite

show abstract

“…In normal oxygen conditions HIF-1α molecule hydroxylates with prolyl hydroxylase (PHD) ferment participation, interacts with protein Von Hippel-Lindau (pVHL), being ubiquitinylated and subjected to proteasomal degradation [13]. Molecular oxygen take part in reaction of hydroxylation, as well as ions of iron and ascorbic acid and in case of insufficiency of one of the components this reaction becomes impossible, leading to increase of HIF-1α number [14]. In case of oxygen insufficiency, two subunits HIF-1α and HIF-1β penetrate into cell nucleus and regulate expression of hundreds target genes, participated in angiogenesis, erythrogenesis, carbohydrate metabolism, cellular proliferation and etc.…”

Section: Actualitymentioning

confidence: 99%

Mechanism of antisurdant action of triazin-indole derivative at experimental acoustic trauma

Пастушенков¹,

Ltd

Kuznecov

et al. 2021

Vestnik SPbSU. Medicine

View full text Add to dashboard Cite

In our research performed using model of acoustic trauma at experimental animals (female of hybrids F1 of CBA and C57BL/6 lines) influence of triazin-indole at expression level of hypoxia induced factor (HIF) in Corti’s organ was studied at its therapy application. As a reference drug cytoflavin was used. Investigated drug in the form of 1 % solution was introduced into animals parenterally in dosage 5, 7, 10 mg/kg with 2 hr intervals after acoustic impact. Injection of cytoflavin as reference drag was performed in 1.7 ml/kg dosage. Level of HIF expression in the drug of Corti’s organ was estimated using immunohistochemical method. It was found out that triazin-indole derivative increases HIF expression in Corti’s cells and in neurons of spiral ganglion at acoustical traumatic impact depending on drug dosage increase. Maximal HIF expression in Corti’s cells and in ganglions were noted at therapeutic dose of the drug 10 mg/kg. In control group and in the group with application citoflavin in dose 1.7 ml/kg minimal HIF expression was observed. According to obtained results of performed investigation the authors concluded that antisurdant property of triazin-indole derivative is realized through the influence on HIF metabolism (probably, by blockage of prolyl hydroxylase) and enables to consider it as a target molecular during the drug application.

show abstract

“…The reaction involves molecular oxygen, iron ions and ascorbic acid. If the quantity of one of these components is insufficient, hydroxylation reaction becomes impossible which results in the increase of HIF-1α quantity [ 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

HIF-1α as a Target Molecule in the Use of Triazino-Indole Derivative on the Acoustic Trauma Model

et al. 2021

View full text Add to dashboard Cite

The effect of triazino-indole derivative (Trisan) on hypoxia-inducible factor (HIF) expression level in the organ of Corti, when administering it for therapeutic and preventive purposes, was investigated using an acoustic trauma model in experimental animals (female F1 hybrids of CBA and C57BL/6 lines). Cytoflavin was used as a comparator product. Study product Trisan (1% solution) was injected intravenously, intramuscularly and intraperitoneally, in the dose of 5, 7 and 10 mg/kg 2 h after the acoustic trauma for therapeutic purposes and in the dose of 5, 7 and 10 mg/kg for 3 days before the acoustic trauma for preventive purposes. IHC methods were used to investigate the organ of Corti. Trisan was observed to increase HIF expression in hair cells and neurons of the spiral ganglion in case of acoustic trauma. Depending on the dose, the increased HIF-1 expression in hair cells and spiral ganglion occurred both after therapeutic and preventive use of Trisan. Maximum HIF expression in hair cells and ganglion was noted at the therapeutic and preventive drug dose of 10 mg/kg. Following experimental results, we conclude that the otoprotective effect of triazino-indole derivative is realized via its effect on HIF metabolism, which makes it a target molecule for the drug.

show abstract

Prolyl hydroxylase domain inhibitors: can multiple mechanisms be an opportunity for ischemic stroke?

Cited by 19 publications

References 145 publications

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light

Photoactivatable Prolyl Hydroxylase 2 Inhibitors for Stabilizing the Hypoxia-Inducible Factor with Light

Mechanism of antisurdant action of triazin-indole derivative at experimental acoustic trauma

HIF-1α as a Target Molecule in the Use of Triazino-Indole Derivative on the Acoustic Trauma Model

Contact Info

Product

Resources

About