TAK1 inhibition mitigates intracerebral hemorrhage-induced brain injury through reduction of oxidative stress and neuronal pyroptosis via the NRF2 signaling pathway

Jing Zhao; Chunli Chen; Lite Ge; Zheng Jiang; Zhiping Hu; Lihong Yin

doi:10.3389/fimmu.2024.1386780

TAK1 inhibition mitigates intracerebral hemorrhage-induced brain injury through reduction of oxidative stress and neuronal pyroptosis via the NRF2 signaling pathway

Front Immunol. 2024 May 2:15:1386780. doi: 10.3389/fimmu.2024.1386780. eCollection 2024.

Authors

Jing Zhao^{1

2}, Chunli Chen^{1

2}, Lite Ge^{1

2}, Zheng Jiang^{1

2}, Zhiping Hu^{1

2}, Lihong Yin^{1

2}

Affiliations

¹ Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China.
² Clinical Medical Research Center for Stroke Prevention and Treatment of Hunan Province, Department of Neurology, Second Xiangya Hospital, Central South University, Changsha, China.

Abstract

Introduction: Intracerebral hemorrhage (ICH) often triggers oxidative stress through reactive oxygen species (ROS). Transforming growth factor-β-activated kinase 1 (TAK1) plays a pivotal role in regulating oxidative stress and inflammation across various diseases. 5Z-7-Oxozeaenol (OZ), a specific inhibitor of TAK1, has exhibited therapeutic effects in various conditions. However, the impact of OZ following ICH and its underlying molecular mechanisms remain elusive. This study aimed to explore the possible role of OZ in ICH and its underlying mechanisms by inhibiting oxidative stress-mediated pyroptosis.

Methods: Adult male Sprague-Dawley rats were subjected to an ICH model, followed by treatment with OZ. Neurobehavioral function, blood-brain barrier integrity, neuronal pyroptosis, and oxidative stress markers were assessed using various techniques including behavioral tests, immunofluorescence staining, western blotting, transmission electron microscopy, and biochemical assays.

Results: Our study revealed that OZ administration significantly inhibited phosphorylated TAK1 expression post-ICH. Furthermore, TAK1 blockade by OZ attenuated blood-brain barrier (BBB) disruption, neuroinflammation, and oxidative damage while enhancing neurobehavioral function. Mechanistically, OZ administration markedly reduced ROS production and oxidative stress by facilitating nuclear factor-erythroid 2-related factor 2 (NRF2) nuclear translocation. This was accompanied by a subsequent suppression of the NOD-like receptor protein 3 (NLRP3) activation-mediated inflammatory cascade and neuronal pyroptosis.

Discussion: Our findings highlight that OZ alleviates brain injury and oxidative stress-mediated pyroptosis via the NRF2 pathway. Inhibition of TAK1 emerges as a promising approach for managing ICH.

Keywords: NLRP3 inflammasome; brain injury; intracerebral hemorrhage; neuroinflammation; oxidative stress; pyroptosis; reactive oxygen species; therapeutic effects.

MeSH terms

Animals
Blood-Brain Barrier / drug effects
Blood-Brain Barrier / metabolism
Brain Injuries / drug therapy
Brain Injuries / etiology
Brain Injuries / metabolism
Cerebral Hemorrhage* / drug therapy
Cerebral Hemorrhage* / metabolism
Disease Models, Animal
Lactones
MAP Kinase Kinase Kinases* / antagonists & inhibitors
MAP Kinase Kinase Kinases* / metabolism
Male
NF-E2-Related Factor 2* / metabolism
Neurons* / drug effects
Neurons* / metabolism
Oxidative Stress* / drug effects
Pyroptosis* / drug effects
Rats
Rats, Sprague-Dawley*
Reactive Oxygen Species / metabolism
Resorcinols
Signal Transduction* / drug effects
Zearalenone / administration & dosage

Substances

MAP kinase kinase kinase 7
Nfe2l2 protein, rat
7-oxozeanol

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (grant numbers 82271367).