title: Bryostatin extends tPA time window to 6 h following middle cerebral artery occlusion in aged female rats.
abstract: Blood-brain barrier (BBB) disruption and hemorrhagic transformation (HT) following ischemic/reperfusion injury contributes to post-stroke morbidity and mortality. Bryostatin, a potent protein kinase C (PKC) modulator, has shown promise in treating neurological injury. In the present study, we tested the hypothesis that administration of bryostatin would reduce BBB disruption and HT following acute ischemic stroke; thus, prolonging the time window for administering recombinant tissue plasminogen activator (r-tPA). Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18-20-month-old female rats using an autologous blood clot with delayed r-tPA reperfusion. Bryostatin (or vehicle) was administered at 2 h post-MCAO and r-tPA was administered at 6 h post-MCAO. Functional assessment, lesion volume, and hemispheric swelling measurements were performed at 24 h post-MCAO. Assessment of BBB permeability, measurement of hemoglobin, assessment of matrix metalloproteinase (MMP) levels by gel zymography, and measurement of PKCε, PKCα, PKCδ expression by western blot were conducted at 24 h post-MCAO. Rats treated with bryostatin prior to r-tPA administration had decreased mortality and hemispheric swelling when compared with rats treated with r-tPA alone. Administration of bryostatin also limited BBB disruption and HT and down-regulated MMP-9 expression while up-regulating PKCε expression at 24 h post-MCAO. Bryostatin administration ameliorates BBB disruption and reduces the risk of HT by down-regulating MMP-9 activation and up-regulating PKCε. In this proof-of-concept study, bryostatin treatment lengthened the time-to-treatment window and enhanced the efficacy and safety of thrombolytic therapy.
authors.affiliation: Department of Neurosurgery, School of Medicine, United States.
authors.forename: Zhenjun
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, School of Medicine, United States.
authors.forename: Brandon P
authors.initials: BP
authors.lastname: Lucke-Wold
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, United States.
authors.forename: Aric F
authors.initials: AF
authors.lastname: Logsdon
authors.affiliation: Department of Neurosurgery, School of Medicine, United States.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Turner
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, United States.
authors.forename: Cong
authors.initials: C
authors.lastname: Tan
authors.affiliation: Department of Neurosurgery, School of Medicine, United States.
authors.forename: Xinlan
authors.initials: X
authors.lastname: Li
authors.affiliation: Blanchette Rockfeller Neuroscience Institute, West Virginia University, United States.
authors.forename: Jarin
authors.initials: J
authors.lastname: Hongpaison
authors.affiliation: Blanchette Rockfeller Neuroscience Institute, West Virginia University, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Alkon
authors.affiliation: Department of Physiology and Pharmacology, School of Medicine, United States.
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
authors.affiliation: Department of Neurosurgery, School of Medicine, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, United States. Electronic address: jdhuber@hsc.wvu.edu.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D054713:Bryostatins / Q000008:administration & dosage*; D002199:Capillary Permeability / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020300:Intracranial Hemorrhages / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D051744:Protein Kinase C-epsilon / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015912:Thrombolytic Therapy; D013997:Time Factors; D061665:Time-to-Treatment; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage*; D015854:Up-Regulation
chemical_list: D054713:Bryostatins; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; C497257:Prkce protein, rat; D051744:Protein Kinase C-epsilon; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9; C572337:Mmp9 protein, rat
keywords: Blood–brain barrier; Bryostatin; Hemorrhagic transformation; MMP-9; Protein kinase C