Application of HIF-1 alpha micromolecule activator FG-4592 for Parkinson's diseases

A dosage form and drug technology, applied in the application field of HIF-1α small molecule activator FG-4592 in Parkinson's disease, can solve the problems of unpublished FG-4592 research, etc. The effect of reducing apoptosis

Inactive Publication Date: 2017-12-15
SHANGHAI FIRST PEOPLES HOSPITAL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

At present, Chinese patent literature mainly discloses some preparation methods of FG-4

Method used

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  • Application of HIF-1 alpha micromolecule activator FG-4592 for Parkinson's diseases
  • Application of HIF-1 alpha micromolecule activator FG-4592 for Parkinson's diseases
  • Application of HIF-1 alpha micromolecule activator FG-4592 for Parkinson's diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1: MPP + Inhibit SH-SY5Y cell proliferation, promote cell apoptosis, affect the expression of HIF-1α

[0028] To assess MPP in SH-SY5Y cells + neurotoxicity, we first used different concentrations (0,1,2,3,4,5mM) of MPP + The cells were treated for 24 hours, and then the cell viability was detected by the CCK-8 method. We found that with a concentration of 3.5 mM MPP + Cell viability dropped to approximately 50% when treated ( figure 1 A), so we choose 3.5mM as the subsequent cell treatment concentration. Our results also show that the MPP + Increase the apoptosis of SH-SY5Y cells ( figure 1 B). Then we detected SH-SY5Y cells in different MPP + Concentration (0.3, 5.5mM) 24 hours and 3.5mM treatment time (0, 6, 12, 24, 36 hours) of HIF-1α protein levels. Such as figure 1 As shown in C and 1D, the protein level of HIF-1α was significantly reduced and exhibited MPP + Dose and time dependent. However, the mRNA expression of HIF-1α was increased ( figur...

Embodiment 2

[0029] Example 2: FG-4592 increases HIF-1α expression and alleviates MPP in SH-SY5Y cells + induced cell damage

[0030] FG-4592 can cause its accumulation by inhibiting the degradation of HIF-1α, and some studies have shown an association between HIF-1α and tyrosine hydroxylase (TH), which is a dopamine (DA) Rate-limiting enzyme for DA synthesis in neurons. Our experiments found that FG-4592 caused a dose-dependent increase in HIF-1α, accompanied by induction of TH ( figure 2 A, 2B). Then the apoptosis of SH-SY5Y was detected after pretreatment with FG-4592. Confirmed by Western-Blot assay, MPP + The increase of the pro-apoptotic protein Bax and the decrease of the anti-apoptotic protein Bcl-2 in SH-SY5Y cells were reversed by FG-4592 pretreatment ( figure 2 C, 2D). AnnexinV-FITC / PI assay showed that when FG-4592 and MPP + When co-treated for 24 hours, the number of apoptotic cells was also significantly reduced ( figure 2 E, 2F). To further study the role of HIF-...

Embodiment 3

[0031] Example 3: Mitochondrial function was significantly improved in dopaminergic neurons treated with FG-4592

[0032] Many studies have shown that mitochondrial dysfunction and oxidative stress may play a key role in the pathogenesis of PD. Dopaminergic neurons are susceptible to oxidative damage due to high levels of reactive oxygen species produced during DA synthesis or its breakdown by monoamine oxidase. We envisioned whether FG-4592 could protect cells by rescuing mitochondrial function. Therefore, we measured mitochondrial membrane potential (MMP) in SH-SY5Y cells co-treated with FG-4592 and MPP+. The results showed that the increase of HIF-1α could partially reverse the decrease of MPP+ caused by cellular MMP ( image 3 A, 3B) and reduction of ATP production ( image 3 C). In order to further explore the changes in the respiratory function of cells, we conducted a real-time analysis of the mitochondrial respiratory function of dopaminergic neurons ( image 3 D)...

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Abstract

The invention relates to a new application of FG-4592, a small molecule activator of HIF-1α, which belongs to the technical field of biomedicine, that is, the application of FG-4592 in the preparation of drugs for treating Parkinson's disease. Its advantages are as follows: the compound is in the third phase of clinical trials, and there is no need to explore its clinical pharmacology and human safety evaluation, which is conducive to the transformation of results. The present invention finds through research in Parkinson's disease cells and animal models that, compared with the model group, the FG-4592 pretreatment group can increase neuron cell viability, reduce cell apoptosis, and can partially reverse the mitochondrial membrane damage caused by neurotoxic drugs. The decrease of electric potential, the decrease of ATP content and the decrease of respiratory function can reduce the damage of MPTP to the dopaminergic neurons in the substantia nigra and striatum of mice, increase the secretion of dopamine and its metabolites in the damaged area, and finally achieve the relief of its movement. Reduced level of function.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to the application of FG-4592, a small molecule activator of HIF-1α, in Parkinson's disease. Background technique [0002] Compound FG-4592, chemical formula: C 19 h 16 N 2 o 5 , CAS No.: 808118-40-3, the structural formula is as shown in formula (I). [0003] [0004] FG-4592 (Roxadustat, also known as Kebomei) and its capsule preparation are the world's first new hypoxia-inducible factor (HIF) in vivo gene regulation technology, through intermittent small-dose oral administration, to achieve biological induction and regulation in vivo, so as to achieve the treatment of kidney disease Anti-anemic drugs for anemia. According to the "Measures for the Administration of Drug Registration", Kebomei and its capsules belong to the domestic Class 1 new drug. It has completed the first and second phase clinical trials, and obtained the approval document for the third phase clini...

Claims

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Application Information

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IPC IPC(8): A61K31/472A61P25/16
CPCA61K31/472
Inventor 吴云成尹慧勇李璇
Owner SHANGHAI FIRST PEOPLES HOSPITAL
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