TAK-3 Inhibits Lipopolysaccharide-Induced Neuroinflammation in Traumatic Brain Injury Rats Through the TLR-4/NF-κB Pathway

Abstract

Pengwei Hou,1,* Yang Yang,2,* Ziqi Li,1,* Dan Ye,2 Li Chen,1 Tianshun Feng,3 Jiateng Zeng,4 Liangfeng Wei,1 Shousen Wang1,5 1Department of Neurosurgery, Fuzong Clinical Medical College of Fujian Medical University (The 900TH Hospital), Fuzhou, Fujian Province, People’s Republic of China; 2Fuzhou General Teaching Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian Province, People’s Republic of China; 3Department of Neurosurgery, Dongfang Affiliated Hospital of Xiamen University School of Medicine, Xiamen University, Xiamen, Fujian Province, People’s Republic of China; 4Department of Neurosurgery, Neurosurgery Research Institute, the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian Province, People’s Republic of China; 5Fujian Provincial Clinical Medical Research Center for Minimally Invasive Diagnosis and Treatment of Neurovascular Diseases, Fuzhou, Fujian Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liangfeng Wei; Shousen Wang, Department of Neurosurgery, Fuzong Clinical Medical College of Fujian Medical University (The 900TH Hospital), No. 156, Xierhuanbei Road, Fuzhou, Fujian Province, 350025, People’s Republic of China, Tel [phone], Email [email protected]; [email protected]: The activation of the inflammatory response is regarded as a pivotal factor in the pathogenesis of TBI. Central nervous system infection often leads to the exacerbation of neuroinflammation following TBI, primarily caused by Gram-negative bacteria. This study aims to elucidate the effects of the novel anti-inflammatory drug TAK-3 on LPS-induced neuroinflammation in TBI rats.Methods: In conjunction with the rat controlled cortical impact model, we administered local injections of Lipopolysaccharide to the impact site. Subsequently, interventions were implemented through intraperitoneal injections of TAK-3 and NF-κB activitor2 to modulate the TLR4/NF-κB axis The impact of LPS on neurological function was assessed using mNSS, open field test, and brain water content measurement. Inflammatory markers, including TNF-α, IL-1β, IL-6 and IL-10 were assessed to evaluate the condition of neuritis by Elisa. The activation of the TLR-4/NF-κB signaling pathway was detected by immunofluorescence staining and Western blot to assess the anti-inflammatory effects of TAK-3.Results: The administration of LPS exacerbated neurological damage in rats with TBI, as evidenced by a reduction in motor activity and an increase in anxiety-like behavior. Furthermore, LPS induced disruption of the blood-brain barrier integrity and facilitated the development of brain edema. The activation of microglia and astrocytes by LPS at the cellular and molecular levels has been demonstrated to induce a significant upregulation of neuroinflammatory factors. The injection of TAK-3 attenuated the neuroinflammatory response induced by LPS.Conclusion: The present study highlights the exacerbating effects of LPS on neuroinflammation in TBI through activation of the TLR-4/NF-κB signaling pathway. TAK-3 can modulate the activity of this signaling axis, thereby attenuating neuroinflammation and ultimately reducing brain tissue damage.Keywords: NF-κB activator2, CNS infection, CCI, inflammation, TAK-3

Keywords

• nf-κb activator2. cns infection. cci. inflammation.tak-3