Ethyl Pyruvate Protects against Blood–Brain Barrier Damage and Improves Long‐term Neurological Outcomes in a Rat Model of Traumatic Brain Injury

摘要

Summary Aims Many traumatic brain injury ( TBI ) survivors sustain neurological disability and cognitive impairments due to the lack of defined therapies to reduce TBI‐induced long‐term brain damage. Ethyl pyruvate ( EP ) has shown neuroprotection in several models of acute brain injury. The present study therefore investigated the potential beneficial effect of EP on long‐term outcomes after TBI and the underlying mechanisms. Methods Male adult rats were subjected to unilateral controlled cortical impact injury. EP was injected intraperitoneally 15 min after TBI and again at 12, 24, 36, 48, and 60 h after TBI. Neurological deficits, blood–brain barrier (BBB) integrity, and neuroinflammation were assessed. Results Ethyl pyruvate improved sensorimotor and cognitive functions and ameliorated brain tissue damage up to 28 day post‐TBI. BBB breach and brain edema were attenuated by EP at 48 h after TBI. EP suppressed matrix metalloproteinase (MMP)‐9 production from peripheral neutrophils and reduced the number of MMP‐9‐overproducing neutrophils in the spleen, and therefore mitigated MMP‐9‐mediated BBB breakdown. Moreover, EP exerted potent antiinflammatory effects in cultured microglia and inhibited the elevation of inflammatory mediators in the brain after TBI. Conclusion Ethyl pyruvate confers long‐term neuroprotection against TBI, possibly through breaking the vicious cycle among MMP‐9‐mediated BBB disruption, neuroinflammation, and long‐lasting brain damage.