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: Gab Seok Kim, Seongeun Cho, James W Nelson, Gregory J Zipfel, Byung Hee Han
• Journal: PloS one (PLoS One) Vol. 9 Issue 2 Pg. e88962 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24551199 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies
• Neuroprotective Agents
• Receptor, trkB
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• Caspase 3

Topics

• Animals
• Animals, Newborn
• Antibodies (administration & dosage, pharmacology)
• Body Temperature (drug effects)
• Caspase 3 (metabolism)
• Cell Survival (drug effects)
• Enzyme Activation (drug effects)
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Hypoxia-Ischemia, Brain (drug therapy, enzymology, pathology, physiopathology)
• Injections, Intraventricular
• Male
• Motor Activity (drug effects)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Phosphorylation (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Receptor, trkB (agonists, metabolism)
• Sensory Receptor Cells (drug effects, enzymology, pathology)