title: Nasal administration of recombinant osteopontin attenuates early brain injury after subarachnoid hemorrhage.
abstract: OBJECTIVE
  Neuronal apoptosis is a key pathological process in subarachnoid hemorrhage (SAH)-induced early brain injury. Given that recombinant osteopontin (rOPN), a promising neuroprotectant, cannot pass through the blood-brain barrier, we aimed to examine whether nasal administration of rOPN prevents neuronal apoptosis after experimental SAH.
  
  
  METHODS
  Male Sprague-Dawley rats (n=144) were subjected to the endovascular perforation SAH model. rOPN was administered via the nasal route and neurological scores as well as brain water content were evaluated at 24 and 72 hours after SAH induction. The expressions of cleaved caspase-3, phosphorylated focal adhesion kinase (FAK), and phosphorylated Akt were examined using Western blot analysis. Neuronal cell death was demonstrated with terminal deoxynucleotid transferase-deoxyuridine triphosphate (dUTP) nick end labeling. We also administered FAK inhibitor 14 and phosphatidylinositol 3-kinase inhibitor, Wortmannin, prior to rOPN to establish its neuroprotective mechanism. ELISA was used to measure rOPN delivery into the cerebrospinal fluid.
  
  
  RESULTS
  Cerebrospinal fluid level of rOPN increased after its nasal administration. This was associated with improved neurological scores and reduced brain edema at 24 hours after SAH. rOPN increased phosphorylated FAK and phosphorylated Akt expressions and decreased caspase-3 cleavage, resulting in attenuation of neuronal cell death within the cerebral cortex. These effects were abolished by FAK inhibitor 14 and Wortmannin.
  
  
  CONCLUSIONS
  Nasal administration of rOPN decreased neuronal cell death and brain edema and improved the neurological status in SAH rats, possibly through FAK-phosphatidylinositol 3-kinase-Akt-induced inhibition of capase-3 cleavage.
authors.affiliation: From the Departments of Physiology and Pharmacology (B.C.T., O.A., K.D., P.R.K., J.Y., J.H.Z.) and Neurosurgery (J.H.Z.), Loma Linda University School of Medicine, CA.
authors.forename: Basak Caner
authors.initials: BC
authors.lastname: Topkoru
authors.forename: Orhan
authors.initials: O
authors.lastname: Altay
authors.forename: Kamil
authors.initials: K
authors.lastname: Duris
authors.forename: Paul R
authors.initials: PR
authors.lastname: Krafft
authors.forename: Junhao
authors.initials: J
authors.lastname: Yan
authors.forename: John H
authors.initials: JH
authors.lastname: Zhang
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000473:pathology; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D053148:Caspase 3 / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D008297:Male; D009474:Neurons / Q000473:pathology; D053495:Osteopontin / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use*; D013345:Subarachnoid Hemorrhage / Q000150:complications / Q000188:drug therapy*; D013997:Time Factors
chemical_list: D047428:Protein Kinase Inhibitors; D011994:Recombinant Proteins; D053495:Osteopontin; D051417:Focal Adhesion Kinase 1; C496052:Ptk2 protein, rat; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; C505410:Casp3 protein, rat; D053148:Caspase 3
keywords: administration, intranasal; apoptosis; early brain injury; recombinant osteopontin; subarachnoid hemorrhage