title: TrkB agonist antibody pretreatment enhances neuronal survival and long-term sensory motor function following hypoxic ischemic injury in neonatal rats.
abstract: Perinatal hypoxic ischemia (H-I) causes brain damage and long-term neurological impairments, leading to motor dysfunctions and cerebral palsy. Many studies have demonstrated that the TrkB-ERK1/2 signaling pathway plays a key role in mediating the protective effect of brain-derived neurotrophic factor (BDNF) following perinatal H-I brain injury in experimental animals. In the present study, we explored the neuroprotective effects of the TrkB-specific agonist monoclonal antibody 29D7 on H-I brain injury in neonatal rats. First, we found that intracerebroventricular (icv) administration of 29D7 in normal P7 rats markedly increased the levels of phosphorylated ERK1/2 and phosphorylated AKT in neurons up to 24 h. Second, P7 rats received icv administration of 29D7 and subjected to H-I injury induced by unilateral carotid artery ligation and exposure to hypoxia (8% oxygen). We found that 29D7, to a similar extent to BDNF, significantly inhibited activation of caspase-3, a biochemical hallmark of apoptosis, following H-I injury. Third, we found that this 29D7-mediated neuroprotective action persisted at least up to 5 weeks post-H-I injury as assessed by brain tissue loss, implicating long-term neurotrophic effects rather than an acute delay of cell death. Moreover, the long-term neuroprotective effect of 29D7 was tightly correlated with sensorimotor functional recovery as assessed by a tape-removal test, while 29D7 did not significantly improve rotarod performance. Taken together, these findings demonstrate that pretreatment with the TrkB-selective agonist 29D7 significantly increases neuronal survival and behavioral recovery following neonatal hypoxic-ischemic brain injury.
authors.affiliation: Department of Pharmacology, Seoul National University, College of Pharmacy, Seoul, Republic of Korea.
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.affiliation: Wyeth Neuroscience Discovery Research, Princeton, New Jersey, United States of America.
authors.forename: Seongeun
authors.initials: S
authors.lastname: Cho
authors.affiliation: Department of Neurological Surgery Washington University School of Medicine, St. Louis, Missouri, United States of America ; Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Nelson
authors.affiliation: Department of Neurological Surgery Washington University School of Medicine, St. Louis, Missouri, United States of America ; Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, Missouri, United States of America ; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Zipfel
authors.affiliation: Department of Pharmacology, Seoul National University, College of Pharmacy, Seoul, Republic of Korea ; Department of Neurological Surgery Washington University School of Medicine, St. Louis, Missouri, United States of America ; Hope Center for Neurological Disorders Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Byung Hee
authors.initials: BH
authors.lastname: Han
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000008:administration & dosage / Q000494:pharmacology*; D001831:Body Temperature / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology* / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000819:agonists* / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*
chemical_list: D000906:Antibodies; D018696:Neuroprotective Agents; D020813:Receptor, trkB; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D053148:Caspase 3