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

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 stu...

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Published in:CNS neuroscience & therapeutics 2015-04, Vol.21 (4), p.374-384
Main Authors: Shi, Hong, Wang, Hai‐Lian, Pu, Hong‐Jian, Shi, Ye‐Jie, Zhang, Jia, Zhang, Wen‐Ting, Wang, Guo‐Hua, Hu, Xiao‐Ming, Leak, Rehana K., Chen, Jun, Gao, Yan‐Qin
Format: Article
Language:English
Subjects:
Animals
Blood-Brain Barrier - drug effects
Blood–brain barrier
Brain - drug effects
Brain - physiopathology
Brain Edema - drug therapy
Brain Edema - physiopathology
Brain Injuries - drug therapy
Brain Injuries - physiopathology
Cells, Cultured
Disease Models, Animal
Ethyl pyruvate
Inflammation
Male
Matrix Metalloproteinase 9 - metabolism
Maze Learning - drug effects
Microglia - drug effects
Microglia - physiology
Neuroimmunomodulation - drug effects
Neuroimmunomodulation - physiology
Neuroprotection
Neuroprotective Agents - pharmacology
Neutrophils - drug effects
Neutrophils - physiology
Original
Pyruvates - pharmacology
Random Allocation
Rats, Sprague-Dawley
Recovery of Function - drug effects
Time Factors
Traumatic brain injury
Treatment Outcome
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Summary: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.
ISSN:1755-5930
1755-5949
DOI:10.1111/cns.12366