Related Experiment Video
Updated: Feb 28, 2026
Author Spotlight: Deciphering Electrical Networks Behind Complex Brain Activities and Disorders
Published on: November 1, 2024
CB2R-mediated GPX4 stabilization: a new avenue for treating cognitive impairment in elderly migraine patients
Xiaowei Fang1, Haonan Ye2,3, Baowen Fan2,3
1Department of Emergency Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China.
Abstract:
Migraine is frequently associated with cognitive impairment, a pathology linked to microglial dysfunction and neuroinflammation. Ferroptosis, a form of iron-dependent lipid peroxidation, driven by the depletion of glutathione peroxidase 4 (GPX4), is increasingly implicated in neurodegenerative processes. This study investigates the protective role of cannabinoid receptor type 2 (CB2R) activation against migraine-associated cognitive deficits by modulating microglial ferroptosis. We demonstrate that CB2R activation, via its agonist JWH133, significantly ameliorates cognitive impairment and synaptic damage in a nitroglycerin-induced migraine model. Mechanistically, JWH133 suppresses microglial ferroptosis by stabilizing GPX4. Our findings reveal that in inflammatory conditions, the E3 ubiquitin ligase Tripartite Motif Containing 33 (TRIM33) mediates the K63-linked polyubiquitination of GPX4, marking it for breakdown via autophagy, a cellular process that degrades unwanted proteins through lysosomes. CB2R activation inhibits TRIM33-GPX4 interaction and subsequent K63-linked ubiquitination, thereby preventing GPX4 degradation and restoring its anti-lipid peroxidation function. This stabilization of GPX4 mitigates mitochondrial dysfunction and lipid peroxidation, as evidenced by lipidomics and mitochondrial assays. Collectively, our study uncovers a novel CB2R-TRIM33-K63 ubiquitination-autophagy axis that critically regulates GPX4 stability and microglial ferroptosis. Targeting this pathway offers a promising therapeutic strategy for mitigating migraine-associated cognitive impairment.
Insights
Cannabinoid receptor type 2 (CB2R) activation protects against migraine-related cognitive deficits by preventing microglial ferroptosis. This involves stabilizing glutathione peroxidase 4 (GPX4) and inhibiting its degradation via a novel CB2R-TRIM33-autophagy pathway.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Migraine is linked to cognitive impairment, microglial dysfunction, and neuroinflammation.
- Ferroptosis, an iron-dependent cell death, is implicated in neurodegeneration and driven by glutathione peroxidase 4 (GPX4) depletion.
- Cannabinoid receptor type 2 (CB2R) activation is explored for its potential to counteract these effects.
Purpose of the Study:
- To investigate the protective role of CB2R activation against migraine-associated cognitive deficits.
- To elucidate the mechanism by which CB2R activation modulates microglial ferroptosis.
- To identify therapeutic targets for migraine-related cognitive impairment.
Main Methods:
- Utilized a nitroglycerin-induced migraine model in rodents.
- Administered a CB2R agonist (JWH133) to assess cognitive function and synaptic damage.
- Investigated the impact of CB2R activation on microglial ferroptosis, GPX4 stability, TRIM33 interaction, ubiquitination, and autophagy.
- Performed lipidomics and mitochondrial assays to evaluate cellular damage.
Main Results:
- CB2R activation significantly ameliorated cognitive impairment and synaptic damage in the migraine model.
- JWH133 suppressed microglial ferroptosis by stabilizing GPX4, preventing its degradation.
- CB2R activation inhibited the interaction between TRIM33 and GPX4, reducing K63-linked ubiquitination and subsequent autophagy-mediated breakdown.
- GPX4 stabilization mitigated mitochondrial dysfunction and lipid peroxidation.
Conclusions:
- CB2R activation offers a neuroprotective effect against migraine-associated cognitive deficits.
- A novel CB2R-TRIM33-K63 ubiquitination-autophagy pathway regulates GPX4 stability and microglial ferroptosis.
- Targeting this pathway presents a promising therapeutic strategy for migraine and associated cognitive impairment.
Related Concept Videos
01:22Alzheimer's Disease: Treatment
01:30Cognitive Enhancers: Cholinesterase Inhibitors and NMDA Receptor Antagonists