Related Experiment Video
Updated: Aug 7, 2026
Quantification of Neurovascular Protection Following Repetitive Hypoxic Preconditioning and Transient Middle Cerebral Artery Occlusion in Mice
Published on: May 4, 2015
TWEAK-Fn14 pathway inhibition protects the integrity of the neurovascular unit during cerebral ischemia
Xiaohui Zhang1, Jeffrey A Winkles, Maria C Gongora
1Department of Neurology and Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA 30322, USA.
Abstract:
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily. TWEAK acts via binding to a cell surface receptor named Fn14. To study the role of this cytokine in the regulation of the permeability of the neurovascular unit (NVU) during cerebral ischemia, TWEAK activity was inhibited in wild-type mice with a soluble Fn14-Fc decoy receptor administered either immediately or 1 h after middle cerebral artery occlusion (MCAO). Administration of Fn14-Fc decoy resulted in faster recovery of motor function and a 66.4%+/-10% decrease in Evans blue dye extravasation when treatment was administered immediately after MCAO and a 46.1%+/-13.1% decrease when animals were treated 1 h later (n=4, P<0.05). Genetic deficiency of Fn14 resulted in a 60%+/-12.8% decrease in the volume of the ischemic lesion (n=6, P<0.05), and a 87%+/-22% inhibition in Evans blue dye extravasation 48 h after the onset of the ischemic insult (n=6, P<0.005). Compared with control animals, treatment with Fn14-Fc decoy or genetic deficiency of Fn14 also resulted in a significant inhibition of nuclear factor-kappaB pathway activation, matrix metalloproteinase-9 activation and basement membrane laminin degradation after MCAO. These findings show that the cytokine TWEAK plays a role in the disruption of the structure of the NVU during cerebral ischemia and that TWEAK antagonism is a potential therapeutic strategy for acute cerebral ischemia.
Insights
Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) disrupts the neurovascular unit during stroke. Inhibiting TWEAK signaling via Fn14 antagonism reduces brain damage and improves recovery after cerebral ischemia.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a cytokine.
- TWEAK signals through the Fn14 receptor.
- The role of TWEAK in cerebral ischemia and neurovascular unit (NVU) integrity is not fully understood.
Purpose of the Study:
- To investigate the role of TWEAK in regulating NVU permeability during cerebral ischemia.
- To evaluate the therapeutic potential of TWEAK antagonism in a mouse model of stroke.
Main Methods:
- Inhibition of TWEAK activity using a soluble Fn14-Fc decoy receptor in wild-type mice subjected to middle cerebral artery occlusion (MCAO).
- Assessment of motor function recovery and Evans blue dye extravasation to measure NVU permeability.
- Evaluation of the effects of genetic Fn14 deficiency on ischemic lesion volume and NVU integrity.
- Analysis of downstream signaling pathways including nuclear factor-kappaB (NF-κB) and matrix metalloproteinase-9 (MMP-9).
Main Results:
- Administration of Fn14-Fc decoy receptor significantly reduced Evans blue dye extravasation and improved motor function recovery.
- Genetic deficiency of Fn14 led to a marked decrease in ischemic lesion volume and NVU permeability.
- TWEAK antagonism inhibited NF-κB activation, MMP-9 activation, and basement membrane laminin degradation.
- Both pharmacological inhibition and genetic deficiency of Fn14 demonstrated protective effects against cerebral ischemia.
Conclusions:
- The TWEAK/Fn14 pathway plays a critical role in the disruption of the NVU during cerebral ischemia.
- TWEAK antagonism represents a promising therapeutic strategy for mitigating brain damage in acute ischemic stroke.
- Targeting the TWEAK pathway may offer neuroprotective benefits by preserving NVU integrity.
