title: Inhibition of p21-Activated Kinase 1 by IPA-3 Promotes Locomotor Recovery After Spinal Cord Injury in Mice.
abstract: METHODS
  Ninety-six male adult CD-1 mice were randomly divided into sham, spinal cord injury (SCI) + vehicle, and SCI + IPA-3 groups. Expression of matrix metalloproteinase (MMP)-2 and MMP-9, production of tumor necrosis factors (TNF)-α and interleukin (IL)-1β, tissue edema, blood-spinal cord barrier penetrability, neural cell apoptosis, and neurological function recovery were measured.
  
  
  OBJECTIVE
  The aim of the study was to evaluate the effect of specific inhibition of p21-activated kinase 1 (PAK1) by IPA-3 on SCI and the underlying mechanisms thereof.
  
  
  BACKGROUND
  SCI is a devastating clinical condition that may result in long-lasting and deteriorating functional deficits. The major goal of SCI treatment is to limit the development of secondary injury. IPA-3, a PAK1 inhibitor, exhibited neuroprotection against secondary damage after traumatic brain injury and subarachnoid hemorrhage (SAH).
  
  
  METHODS
  MMP-2, MMP-9, and cleaved caspase-3 expression were assessed by Western blot. Inflammatory cytokines TNF-α and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). The blood-spinal cord barrier disruption was measured by water content and Evans blue extravasation of the spinal cord. Neuronal apoptosis was evaluated by Nissl staining and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay. The locomotor behavior of hind limb was evaluated by Basso Mouse Scale (BMS) at 1, 3, 7, 14, and 28 days post-injury.
  
  
  RESULTS
  Compared with SCI + vehicle mice, IPA-3 treatment showed decreased p-PAK1, MMP-2, MMP-9, cleaved caspase-3, TNF-α, and IL-1β expression. Moreover, inhibition of PAK1 by IPA-3 reduced spinal cord water content and Evans blue extravasation, increased neuronal survival, and reduced TUNEL-positive cells at 24 hours after SCI. Furthermore, IPA-3 improved spinal cord functional recovery 7 days after SCI.
  
  
  CONCLUSIONS
  Inhibition of PAK1 by IPA-3 promoted recovery of neurological function, possibly by downregulating the expression of MMP-2, MMP-9, TNF-α, and IL-1β. Our data suggest that PAK1 may be a potential therapeutic target in patients with SCI.
  
  
  METHODS
  1.
authors: Department of Orthopaedic Surgery, The General Hospital of People's Liberation Army (301 Hospital), Wukesong, Beijing, China.
authors: Xinran
authors: X
authors: Ji
authors: Yiling
authors: Y
authors: Zhang
authors: Lihai
authors: L
authors: Zhang
authors: Hua
authors: H
authors: Chen
authors: Ye
authors: Y
authors: Peng
authors: Peifu
authors: P
authors: Tang
mesh_terms: D000818:Animals; D004220:Disulfides / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009284:Naphthols / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004220:Disulfides; C541795:IPA-3 compound; D009284:Naphthols; D047428:Protein Kinase Inhibitors; C515905:Pak1 protein, mouse; D054462:p21-Activated Kinases