title: Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke.
abstract: OBJECTIVE
  Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator reperfusion in aged rats.
  
  
  METHODS
  Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18- to 20-month-old female Sprague-Dawley rats using an autologous blood clot with tissue plasminogen activator-mediated reperfusion. Bryostatin was administered at 6 hours post-MCAO, then at 3, 6, 9, 12, 15, and 18 days after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 days after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 days post-MCAO. Histological assessment of PKC isozymes was performed at 24 hours post-MCAO.
  
  
  RESULTS
  Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 days. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 days post-MCAO. Changes in αPKC expression and εPKC expression in neurons were noted in bryostatin-treated rats at 24 hours post-MCAO.
  
  
  CONCLUSIONS
  Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome after MCAO.
authors.affiliation: From the Department of Neurosurgery, School of Medicine (Z.T., R.C.T., R.L.L., X.L., Z.J.N., C.L.R.), Blanchette Rockefeller Neuroscience Institute (J.H., W.Z., D.L.A.), and Department of Basic Pharmaceutical Science, School of Pharmacy (A.F.L., J.D.H.), West Virginia University Health Sciences Center, Morgantown, WV.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Tan
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Turner
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Leon
authors.forename: Xinlan
authors.initials: X
authors.lastname: Li
authors.forename: Jarin
authors.initials: J
authors.lastname: Hongpaisan
authors.forename: Wen
authors.initials: W
authors.lastname: Zheng
authors.forename: Aric F
authors.initials: AF
authors.lastname: Logsdon
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Naser
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001253:Astrocytes / Q000187:drug effects / Q000473:pathology; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D054713:Bryostatins / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D015996:Survival Rate
chemical_list: D054713:Bryostatins; D047428:Protein Kinase Inhibitors; D011493:Protein Kinase C
keywords: aging; blood-brain barrier; infarction; protein kinase C; tissue plasminogen activator