CN-122005806-A - Application of biliverdin reductase inhibitor in preparation of medicine for treating cerebral arterial thrombosis

Abstract

The invention provides application of an inhibitor of biliverdin reductase in preparing a medicament for treating hemorrhagic stroke, relates to the technical field of biological medicines, and firstly reveals pathological nuclear translocation of the biliverdin reductase in the hemorrhagic stroke, and activates lipid peroxidation pathway by co-localization with lipid metabolism key enzyme ACSL4 to drive neuronal iron death; according to the method, the biliverdin reductase is provided as a novel therapeutic target, and the inhibitor can specifically block the expression or nuclear shift of the biliverdin reductase, so that on the premise of not obviously interfering the physiological cytoplasmic antioxidant function of the biliverdin reductase, the iron overload is effectively relieved, the lipid peroxidation is improved, the GPX4 expression is recovered, the iron death of nerve cells is reduced, finally the neurological defect of an animal model is obviously improved, and the method has the advantages of novel mechanism, verifiability of curative effect, targeting accuracy and clinical safety for avoiding the risk of high bilirubin toxicity.

Inventors

• CHEN YING
• Lang Dongcen
• LI ZHENG
• LI LI
• ZHENG YANNING
• ZHANG JING
• DUAN ZIHENG
• NIU MENGYU
• SHI CHENYANG

Assignees

• 河南师范大学

Dates

Publication Date

20260512

Application Date

20260318

Claims (10)

1. 1. Application of biliverdin reductase inhibitor in preparing medicine for treating cerebral arterial thrombosis is provided.
2. 2. The use according to claim 1, wherein the inhibitor of biliverdin reductase comprises the following (a) - (c): (a) Substances inhibiting the activity of biliverdin reductase protein; (b) Substances that inhibit the expression of genes encoding biliverdin reductase; (c) Substances inhibiting nuclear translocation of biliverdin reductase.
3. 3. The composition of claim 2, wherein the substance that inhibits the activity of a biliverdin reductase protein and/or the substance that inhibits nuclear translocation of a biliverdin reductase comprises epigallocatechin gallate.
4. 4. The use according to claim 2, wherein the substance inhibiting the expression of the gene encoding the biliverdin reductase comprises siRNA.
5. 5. The use according to claim 4, wherein the siRNA comprises a double stranded RNA consisting of two single stranded RNAs as shown in SEQ ID NO.1 and SEQ ID NO. 2.
6. 6. The use according to claim 1, further characterized in that the inhibitor of biliverdin reductase effects treatment of hemorrhagic stroke by (i) to (iv) as follows: (i) The iron overload is relieved; (ii) Improving lipid peroxidation; (iii) Reducing neuronal iron death; (iv) Improving nerve function deterioration.
7. 7. The use according to any one of claims 1 to 6, wherein the biliverdin reductase comprises biliverdin reductase a.
8. 8. A medicament for treating hemorrhagic stroke, characterized in that the medicament comprises an inhibitor of a biliverdin reductase.
9. 9. The medicament of claim 8, wherein the inhibitor of biliverdin reductase comprises the following (a) - (c): (a) Substances inhibiting the activity of biliverdin reductase protein; (b) Substances that inhibit the expression of genes encoding biliverdin reductase; (c) Substances that inhibit nuclear translocation of biliverdin reductase; preferably, the (a) and/or (c) is epigallocatechin gallate; Preferably, the (b) is a substance that inhibits the expression of a gene encoding a biliverdin reductase; Preferably, the substance that inhibits the expression of a gene encoding a biliverdin reductase comprises an siRNA; preferably, the siRNA comprises a double stranded RNA consisting of two single stranded RNAs as shown in SEQ ID NO.1 and SEQ ID NO. 2.
10. 10. The medicament according to any of claims 8 to 10, characterized in that said biliverdin reductase comprises biliverdin reductase a.

Description

Application of biliverdin reductase inhibitor in preparation of medicine for treating cerebral arterial thrombosis Technical Field The invention relates to the technical field of biological medicines, in particular to application of a biliverdin reductase inhibitor in preparation of a medicine for treating cerebral arterial thrombosis. Background Hemorrhagic stroke is an acute cerebrovascular disease in which cerebral vessels are ruptured due to non-trauma and blood accumulation causes brain tissue injury, and comprises two major types of cerebral hemorrhage and subarachnoid hemorrhage. Although the incidence of age-standardized cerebral arterial thrombosis is in a decreasing trend and lower than that of ischemic cerebral arterial thrombosis, the mortality disability rate is far higher than that of ischemic cerebral arterial thrombosis. Currently, relatively effective clinical treatments for acute hemorrhagic stroke mainly include surgical procedures and hemostatic treatments. However, there is little success due to the narrow therapeutic window and the risk of ischemia/reperfusion injury. Thus, new therapeutic strategies are urgently needed. The damage of hemorrhagic stroke to the nervous system includes the first damage caused by blood bursting through blood vessels and the second damage caused by hemoglobin and metabolites thereof in erythrocytes, etc. Studies have demonstrated that hemoglobin induces cell death in both in vivo and in vitro experiments, and the form of cell death involved encompasses a variety of mechanisms including apoptosis, autophagy, and iron death. Heme in hemoglobin is metabolized in the body into Fe 2+、CO2 and biliverdin. Scott j Dixion was equal to 2012, the first proposal that iron death is a form of iron ion-dependent cell death, and has significant differences from classical apoptosis, pyro-apoptosis, autophagy, necrotic apoptosis, etc., and is specifically represented by accumulation of excessive iron ions, lipid peroxides and related metabolites in cells, and peroxidation of polyunsaturated fatty acids (PUFA) of plasma membranes can occur. Iron overload following hemorrhagic stroke undoubtedly promotes lipid peroxidation by causing the accumulation of Reactive Oxygen Species (ROS) through the fenton reaction. Studies have shown that iron death is associated with a variety of diseases, such as infections, autoimmune diseases, neurodegenerative diseases, cerebrovascular diseases, and tumors. However, the specific mechanism of iron death in hemorrhagic stroke is not yet understood. In view of this, the present invention has been made. Disclosure of Invention The invention aims to provide an application of a biliverdin reductase inhibitor in preparing a medicament for treating cerebral arterial thrombosis, which at least solves one of the technical problems in the prior art. The second object of the present invention is to provide a medicament for treating cerebral arterial thrombosis. In order to achieve the above object of the present invention, the following technical solutions are specifically adopted: the invention provides an application of a biliverdin reductase inhibitor in preparing a medicament for treating cerebral arterial thrombosis. Further, the biliverdin reductase inhibitor comprises the following (a) - (c): (a) Substances inhibiting the activity of biliverdin reductase protein; (b) Substances that inhibit the expression of genes encoding biliverdin reductase; (c) Substances inhibiting nuclear translocation of biliverdin reductase. Further, the substance inhibiting the activity of the biliverdin reductase protein includes epigallocatechin gallate. Further, the substance inhibiting the expression of the gene encoding the biliverdin reductase includes siRNA. Further, the siRNA comprises double-stranded RNA consisting of two single-stranded RNAs shown in SEQ ID NO.1 and SEQ ID NO. 2. Furthermore, the biliverdin reductase inhibitor can treat hemorrhagic cerebral apoplexy by the following (i) - (iv): (i) The iron overload is relieved; (ii) Improving lipid peroxidation; (iii) Reducing neuronal iron death; (iv) Improving nerve function deterioration. Further, the biliverdin reductase comprises biliverdin reductase A. The invention also provides a medicament for treating cerebral arterial thrombosis, which comprises an inhibitor of a biliverdin reductase. Further, the biliverdin reductase inhibitor comprises the following (a) - (c): (a) Substances inhibiting the activity of biliverdin reductase protein; (b) Substances that inhibit the expression of genes encoding biliverdin reductase; (c) Substances that inhibit nuclear translocation of biliverdin reductase; preferably, the (a) and/or (c) is epigallocatechin gallate; Preferably, the (b) is a substance that inhibits the expression of a gene encoding a biliverdin reductase; Preferably, the substance that inhibits the expression of a gene encoding a biliverdin reductase comprises an siRNA; preferably, the siRNA comprises a