Therapeutic potential of a TrkB agonistic antibody for ischemic brain injury

• Main Authors: Fang Han, Xiaoming Guan, Wei Guo, Bai Lu
• Format: Article
• Language: English
• Published: Elsevier 2019-07-01
• Series: Neurobiology of Disease
• Subjects: Receptor tyrosine kinase; TrkB agonist; Monoclonal antibody; Drug discovery; Stroke; Apoptosis
• Online Access: http://www.sciencedirect.com/science/article/pii/S0969996119300993

The clinical trials employing neuroprotectants targeting single, early pathogenic mechanisms in stroke have so far been barely successful. We found in human postmortem stroke brains that in addition to apoptosis, necroptosis also contributed to neuronal damage. Thus, a new strategy targeting both mechanisms might be necessary. While brain-derived neurotrophic factor (BDNF) is a potent survival factor for neurons, its poor bioavailability including low diffusion rate and short half-life makes it unlikely a therapeutic agent. We recently developed a TrkB agonistic antibody (Ab4B19) that mimicked BDNF functionally but exhibited better physicochemical and pharmacological features. We showed that Ab4B19 halted neuronal death in vitro under multiple conditions that simulate ischemia/reperfusion injury, including oxygen-glucose deprivation (OGD), glutamate toxicity, oxidative stress and nutrient deprivation. In a rat model of ischemia/reperfusion, Ab4B19 suppressed both apoptosis and necroptosis, leading to a reduction in infarct volume and acceleration of functional recovery from sensorimotor impairments. In neurons derived from human embryonic stem cells (hESCs), Ab4B19 activated TrkB and its downstream signaling, and rescued neuronal death from OGD at a similar level as that in mouse neurons. Together, our study revealed necroptosis in human stroke brain, and demonstrated a BDNF-based strategy targeting both apoptosis and necroptosis for ischemic stroke treatment.