Kaempferol attenuates secondary brain injury after traumatic brain injury in mice with reduced neuroinflammation

Traumatic brain injury (TBI) triggers a secondary injury cascade characterized by neuroinflammation, blood-brain barrier disruption, cerebral hypoperfusion, and progressive neuronal loss, yet effective therapies remain limited. Here, we investigated whether kaempferol attenuates secondary brain injury after TBI in mice by suppressing neuroinflammation. Using a fluid percussion injury model, we performed transcriptomic, histological, behavioral, cerebral perfusion, flow cytometric, and protein analyses.

Kaempferol treatment reduced lesion burden, tissue disruption, and Evans blue extravasation, and improved neurological, motor, and cognitive outcomes after TBI. It also decreased neuronal loss and neuronal apoptosis in the injured cortex and hippocampus. Notably, kaempferol reduced microglial accumulation and neutrophil infiltration and was associated with a less pro-inflammatory microglial cytokine profile, including reduced IL-1β and TNF-α expression and increased IL-4 and TGF-β expression.

And in vitro, kaempferol attenuated LPS-induced pro-inflammatory activation of BV2 microglial cells. In addition, kaempferol increased CD31 immunoreactivity, restored ZO-1 immunoreactivity along CD31-positive microvessels, improved ipsilateral cortical blood flow, and was accompanied by increased expression of PI3K, p-AKT, HIF-1α, VEGF, HO-1, and Bcl-2, together with reduced Bax and cleaved caspase-3. These findings indicate that kaempferol attenuates secondary brain injury after TBI in mice, with reduced neuroinflammation, oxidative stress, BBB disruption, vascular dysfunction, and neuronal apoptosis as prominent associated features.

Thank all members of the laboratory for their technical assistance and helpful discussions. We also thank the staff of the animal facility of Tianjin Medical University General Hospital for their support with animal care. This work was supported by the Tianjin Health Research Project (Grant NO.TJWJ2026MS031), the Joint Funds of the Natural Science Foundation of Tianjin (No.25JCLZJC00010), and the Scientific Research Program of Tianjin Municipal Education Commission (No.2024KJ248), Department of Neurosurgery, Tianjin HuanHu Hospital, Tianjin, 300000, China Tuo Li, Dianyi Wang, Lei Li, Ruilong Peng, Guobin Zhang & Hongguang Wang Tianjin Institute of Neurosurgery, Tianjin, 300000, China Tuo Li, Lei Li, Ruilong Peng, Guobin Zhang & Hongguang Wang Tianjin Key Laboratory of Cerebral Vascular and Neurodegenerative Diseases, Tianjin, 300000, China Tianjin Key Laboratory of Cerebral Blood Flow Reconstruction and Head and Neck Tumor NewTechnology, Tianjin, 300000, China Tianjin Medical University, Tianjin, 300000, China Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300000, China Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education, Tianjin, 300000, China Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, 300000, China Department of Neurology, Tianjin HuanHu Hospital, Tianjin, 300000, China Correspondence to Guobin Zhang or Hongguang Wang.

The authors declare no competing interests. All animal experiments were reviewed and approved by the Animal Ethics Committee of Tianjin Medical University General Hospital (approval no. IRB2020-DW-19) and were conducted in accordance with the institutional guidelines for the care and use of laboratory animals.

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