Osthole confers neuroprotection against cortical stab wound injury and attenuates secondary brain injury.
BACKGROUND
Neuroendoscopy is an innovative technique for neurosurgery that can nonetheless result in traumatic brain injury. The accompanying neuroinflammation may lead to secondary tissue damage, which is the major cause of delayed neuronal death after surgery. The present study investigated the capacity of osthole to prevent secondary brain injury and the underlying mechanism of action in a mouse model of stab wound injury.


METHODS
A mouse model of cortical stab wound injury was established by inserting a needle into the cerebral cortex for 20 min to mimic neuroendoscopy. Mice received an intraperitoneal injection of osthole 30 min after surgery and continued for 14 days. Neurological severity was evaluated 12 h and up to 21 days after the trauma. Brains were collected 3-21 days post-injury for histological analysis, immunocytochemistry, quantitative real-time PCR, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and enzyme-linked immunosorbent assays.


RESULTS
Neurological function improved in mice treated with osthole and was accompanied by reduced brain water content and accelerated wound closure relative to untreated mice. Osthole treatment reduced the number of macrophages/microglia and peripheral infiltrating of neutrophils and lowered the level of the proinflammatory cytokines interleukin-6 and tumor necrosis factor α in the lesioned cortex. Osthole-treated mice had fewer TUNEL+ apoptotic neurons surrounding the lesion than controls, indicating increased neuronal survival.


CONCLUSIONS
Osthole reduced secondary brain damage by suppressing inflammation and apoptosis in a mouse model of stab wound injury. These results suggest a new strategy for promoting neuronal survival and function after neurosurgery to improve long-term patient outcome.
Department of Engineering, University of Oxford, Oxford, OX1 3LZ, UK. yang.xia@stx.ox.ac.uk.
Yang
Y
Xia
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. 1150031769@qq.com.
Liang
L
Kong
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. yaoyj23@qq.com.
Yingjia
Y
Yao
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. jolene.jiao@163.com.
Yanan
Y
Jiao
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. 35192153@qq.com.
Jie
J
Song
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. 444167270@qq.com.
Zhenyu
Z
Tao
Department of Engineering, University of Oxford, Oxford, OX1 3LZ, UK. zhong.you@eng.ox.ac.uk.
Zhong
Z
You
School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian, 116600, China. jingxianyang@yahoo.com.
Jingxian
J
Yang
D000704:Analysis of Variance; D000818:Animals; D001929:Brain Edema / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D053148:Caspase 3 / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D003374:Coumarins / Q000627:therapeutic use*; D016207:Cytokines; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000209:etiology / Q000517:prevention & control*; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009460:Neurologic Examination; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors
D003374:Coumarins; D016207:Cytokines; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D009195:Peroxidase; D053148:Caspase 3; C046627:osthol