Related Experiment Video
Updated: Sep 17, 2025
Evaluating Cell Death Signaling by Immunofluorescence in a Rat Model of Ischemic Stroke
Published on: January 3, 2025
Targeting RIPK1-mediated necroptosis, oxidative stress, and ferroptosis: A novel multitarget therapy for ischemic
Ziwei Song1, Liang Ye2, Yunjie Wang1
1School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs in Universities of Shandong, Yantai University, Yantai, 264005, China; State Key Laboratory of Advanced Drug Delivery and Release Systems, Shandong Luye Pharmaceutical Co., Ltd., Yantai, Shandong, 264003, China.
Abstract:
Ischemic stroke is characterized by high mortality and disability rates, and involves complex pathological processes mediated by multiple damage cascade mechanisms. While current clinical investigational drugs predominantly target antioxidant stress pathways, there remains an urgent need for multi-target therapeutic agents with enhanced therapeutic potential. Notably, RIPK1-mediated necroptosis and neuroinflammation have emerged as critical drivers of secondary brain injury, impacting stroke severity and clinical prognosis. Guided by these mechanistic insights, we rationally designed and synthesized a structurally diverse series of novel 4,5-dihydro-1H-pyrazole derivatives, followed by comprehensive biological evaluations. Compound 23a demonstrated potent RIPK1 kinase inhibitory activity (IC50 = 0.115 μM), and exhibited superior antioxidant efficacy (IC50 = 9.72 μM) compared to the clinically approved drug edaravone (IC50 = 22.79 μM). Furthermore, 23a demonstrated remarkable anti-ferroptosis activity by suppressing PTGS2 mRNA expression (IC50 = 0.156 μM). In vivo studies showed that 23a markedly reduced cerebral infarction volume and improved neurological function scores in transient middle cerebral artery occlusion (tMCAO) model, outperforming edaravone, and demonstrated multi-target effects against oxidative stress, necroptosis, and ferroptosis in the ischemic penumbra tissue. These findings collectively highlight 23a as a promising triple-target lead compound for ischemic stroke therapy, warranting further optimization and development.
Insights
A novel compound, 23a, shows promise for treating ischemic stroke by targeting oxidative stress, necroptosis, and ferroptosis. It outperformed edaravone in preclinical models, reducing brain damage and improving function.
Area of Science:
- Neuroscience
- Medicinal Chemistry
- Pharmacology
Background:
- Ischemic stroke leads to high mortality and disability due to complex pathological processes.
- Current treatments primarily target antioxidant stress, necessitating multi-target agents.
- RIPK1-mediated necroptosis and neuroinflammation are key drivers of secondary brain injury in stroke.
Purpose of the Study:
- To design and synthesize novel 4,5-dihydro-1H-pyrazole derivatives as potential multi-target therapeutics for ischemic stroke.
- To evaluate the efficacy of these compounds against key pathological pathways including oxidative stress, necroptosis, and ferroptosis.
Main Methods:
- Rational design and synthesis of novel 4,5-dihydro-1H-pyrazole derivatives.
- In vitro biological evaluation of RIPK1 kinase inhibitory activity, antioxidant efficacy, and anti-ferroptosis activity.
- In vivo assessment using a transient middle cerebral artery occlusion (tMCAO) model in rodents.
Main Results:
- Compound 23a exhibited potent RIPK1 kinase inhibition (IC50 = 0.115 μM).
- 23a demonstrated superior antioxidant efficacy (IC50 = 9.72 μM) compared to edaravone (IC50 = 22.79 μM).
- 23a showed significant anti-ferroptosis activity by suppressing PTGS2 mRNA (IC50 = 0.156 μM) and reduced cerebral infarction volume and improved neurological function in vivo.
Conclusions:
- Compound 23a acts as a promising triple-target lead compound for ischemic stroke therapy.
- 23a demonstrates multi-target effects against oxidative stress, necroptosis, and ferroptosis.
- Further optimization and development of 23a are warranted for clinical application.
Related Concept Videos
01:16Necrosis
Morphological Manifestations of Necrosis
Necrotic cells show different types of morphological appearance depending on the type of tissue and infection. In coagulative necrosis, cells become...
01:46Electron Transport Chain: Complex I and II
ROS generation is regulated and maintained at moderate levels necessary...