Inhibition of p21-activated kinase 1 by IPA-3 attenuates secondary injury after traumatic brain injury in mice.

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.