title: Inhibition of p21-activated kinase 1 by IPA-3 attenuates secondary injury after traumatic brain injury in mice.
abstract: The p21-activated kinase 1 (PAK1) is up-regulated in the brain following traumatic brain injury (TBI). Inhibition of PAK1 has been found to alleviate brain edema in a rat model of subarachnoid hemorrhage. Suppressing PAK1 activity might represent a novel therapeutics of attenuating secondary injury following TBI. Here we confirmed that the mRNA and protein levels of PAK1 and the protein level of p-PAK1 were significantly increased after inducing TBI in mice via M.A. Flierl's weight-drop model. A single intraperitoneal administration of IPA-3, a specific PAK1 inhibitor, immediately after TBI significantly reduced the protein level of p-PAK1, cleaved caspase-3 level, the number of apoptotic cells at the lesion sites of TBI mice. It also reduced brain water content and the blood-brain barrier permeability in TBI mice. Furthermore, the administration of IPA-3 significantly reduced the neurological severity score and increased the grip test score in TBI mice. Taken together, we demonstrate that PAK1 inhibition by IPA-3 may attenuate the secondary injury following TBI, suggesting it might be a promising neuroprotective strategy for preventing the development of secondary injury after TBI.
authors.affiliation: The General Hospital of People's Liberation Army (301 Hospital), 28 Fuxing Road, Wukesong, Beijing 100000, China.
authors.forename: Xinran
authors.initials: X
authors.lastname: Ji
authors.affiliation: The General Hospital of People's Liberation Army (301 Hospital), 28 Fuxing Road, Wukesong, Beijing 100000, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The General Hospital of People's Liberation Army (301 Hospital), 28 Fuxing Road, Wukesong, Beijing 100000, China.
authors.forename: Lihai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The General Hospital of People's Liberation Army (301 Hospital), 28 Fuxing Road, Wukesong, Beijing 100000, China.
authors.forename: Licheng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: The General Hospital of People's Liberation Army (301 Hospital), 28 Fuxing Road, Wukesong, Beijing 100000, China.
authors.forename: Yiling
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The General Hospital of People's Liberation Army (301 Hospital), 28 Fuxing Road, Wukesong, Beijing 100000, China. Electronic address: ortho301@163.com.
authors.forename: Peifu
authors.initials: P
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001812:Blood-Brain Barrier / Q000187:drug effects; D001929:Brain Edema / Q000517:prevention & control; D001930:Brain Injuries / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D004220:Disulfides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009284:Naphthols / Q000494:pharmacology*; D010766:Phosphorylation; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D004220:Disulfides; C541795:IPA-3 compound; D009284:Naphthols; D054462:p21-Activated Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: BBB disruption; Brain edema; IPA-3; Neurological functions; PAK1; Traumatic brain injury