CN-122005546-A - Application of brucine compounds in preparation of medicines for treating acute cerebral ischemic stroke

Abstract

The invention discloses an application of an brucine compound in preparing a medicament for treating acute cerebral ischemic stroke. The invention provides application of brucea javanica E in preparing medicines for inhibiting PARthanatos and further provides application of brucea javanica E in preparing medicines for treating cerebral apoplexy, medicines for treating cerebral ischemia reperfusion injury and PARP-1 inhibitors. The invention screens and identifies brucea javanica bitter element E to become a strong inhibitor of PARthanatos under nanomolar concentration because of inhibiting PARP-1 overactivation. Brucea javanica bitter E effectively prevents accumulation of PAR modified proteins, relieves mitochondrial membrane potential collapse and inhibits AIF nuclear translocation. Brucea javanica kutin E can greatly reduce infarct volume and denatured neurons, increases microvascular density, has no adverse effect on cerebral blood flow, and has single, delayed and low-dose central protection potential.

Inventors

• SHEN YUXIN
• ZHANG CHUFENG
• XU XIAOHUI

Assignees

• 皖南医学院

Dates

Publication Date

20260512

Application Date

20260311

Claims (10)

1. 1. Application of brucine compound containing kudzin diterpenoid nucleus in preparing medicines for inhibiting PARthanatos is provided.
2. 2. The use according to claim 1, wherein the brucea compound comprises at least one of brucea javanica E, pasakbumin B, 13, 21-dihydro wide-tasone, brucea javanica D, brucea lactone a.
3. 3. The use of claim 1, wherein PARthanatos is PARthanatos resulting from cerebral ischemic stroke.
4. 4. Use of brucea javanica bitter element E in any one of the following: (1) Preparing a cerebral apoplexy treatment medicine; (2) Preparing a cerebral ischemia reperfusion injury treatment drug; (3) Preparing a poly (ADP-ribose) polymerase 1 inhibitor; (4) Preparing a medicament for preventing accumulation of PAR modified proteins; (5) Preparing a medicament for slowing down the breakdown of mitochondrial membrane potential; (6) Preparing the medicine for inhibiting the nuclear translocation of AIF.
5. 5. The use according to claim 4, wherein the stroke is an acute cerebral ischemic stroke.
6. 6. A poly (ADP-ribose) polymerase 1 inhibitor containing brucea javanica E.
7. 7. PARthanatos inhibitor containing brucea javanica extract E.
8. 8. A cerebral apoplexy therapeutic agent containing brucea javanica E.
9. 9. The medicament or inhibitor according to any of claims 6 to 8, characterized in that the concentration of brucea javanica E is at least 800nM.
10. 10. The medicament or inhibitor according to claim 9, characterized in that the concentration of brucea javanica E is 1-30 μm.

Description

Application of brucine compounds in preparation of medicines for treating acute cerebral ischemic stroke Technical Field The invention relates to a medicament for treating acute cerebral ischemic stroke, in particular to application of an brucine compound in preparing the medicament for treating acute cerebral ischemic stroke. Background Ischemic stroke, also known as Cerebral Ischemic Stroke (CIS), is one of the leading causes of death. In 2021, the global ischemic stroke has the number of 780 Mo Xin cases, which account for more than 65% of all cases. The pathophysiology of ischemic stroke is characterized by about 190 tens of thousands of neurons lost per minute after the event, with irreversible damage to brain tissue occurring within six hours. Despite advances in therapeutic approaches such as revascularization, over 50% of patients remain significantly disabled after intervention. Although venous thrombolysis and mechanical thrombolysis can recanalize occluded blood vessels, the curative effect is limited by a narrow treatment window of 4.5 hours, reperfusion injury and hemorrhage transformation present significant challenges, and the actual benefit is less than 20 percent of people. The more urgent problem is the lack of neuroprotective drugs currently being validated by evidence-based medicine that can improve prognosis and are marketed. Since the 70 th century of 20 th century, researchers have explored over 1,000 candidate molecules including the free radical scavenger NXY-059, magnesium agents, calcium antagonists and excitotoxic inhibitors such as NA-1 and GABA modulators S44819. Although these drug candidates were encouraging in animal models, they all frequently failed in phase III clinical trials. The fundamental problem is that the prior art still cannot effectively target the "irrecoverable" link in the ischemia cascade. Recent developments in cell death biology have led to the interest in the cell death process mediated by poly (ADP-ribose) polymer accumulation (PARthanatos). Unlike classical cell death forms such as apoptosis, necrosis or pyro-death, PARthanatos are initiated by excessive activation of poly (ADP-ribose) polymerase-1 (PARP-1) by DNA single strand breaks, which are manifested by accumulation of PAR polymers, increased mitochondrial membrane permeability, translocation of apoptosis-inducing factors (AIF) to the nucleus, ultimately leading to extensive DNA breaks and energy depletion. Morphologically, PARthanatos is characterized by a concentration of nuclei without caspase activation, which occurs spatially from the neuronal nuclei prior to membrane rupture, and is thus considered to be the "first wave" cell death following an ischemic event. Notably, once initiated, PARthanatos also failed to inhibit other cell death pathway blockers, highlighting its critical role in neuronal death following cerebral ischemia. Studies using transgenic mouse models indicate that knockout of PARP-1 or mutant AIF nuclear localization sequences can significantly reduce infarct volume by 40% -60% without affecting cerebral blood flow, suggesting that targeting PARthanatos pathways have potential therapeutic value. Unfortunately, currently clinically used PARP inhibitors such as olapari have greater systemic toxicity and poor central permeability, and have not been tested in the stroke field. Traditional Chinese medicine has unique advantages due to multiple components, multiple targets and low toxicity, and modern pharmacological studies prove that compounds such as quercetin, resveratrol, silymarin and flavonoid can cross the blood brain barrier, indirectly inhibit PARP-1 enzyme activity at micromolar concentration and reduce PAR polymer level. However, these findings focused mainly on the effects of PAR modification, lack of comprehensive screening and evaluation for PARthanatos signaling pathways, and their site of action, structure-activity relationship, in vivo efficacy window and safety profile remain under-described. The brucine compound is extracted from dry mature fruits of brucea javanica (Brucea javanica), and is applied to preparation of antitumor drugs due to strong cytotoxicity. Some current research results (reference ：Lan X, Wang Q, Liu Y, You Q, Wei W, Zhu C, Hai D, Cai Z, Yu J, Zhang J, Liu N. Isoliquiritigenin alleviates cerebral ischemia-reperfusion injury by reducing oxidative stress and ameliorating mitochondrial dysfunction via activating the Nrf2 pathway. Redox Biol. 2024 Nov;77:103406. doi: 10.1016/j.redox.2024.103406. Epub 2024 Oct 22. PMID: 39454290; PMCID: PMC11546133.） shows that brucea javanica, as an Nrf2 inhibitor, can reverse the mitochondrial protection property and anti-apoptosis effect of isoliquiritigenin in vivo and in vitro, and cancel the potential neuroprotection effect of isoliquiritigenin on cerebral ischemia injury, in addition, more references also prove that brucea javanica is a medicament for promoting stroke injury exacerbation, the mechanism is