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.