Blood-brain barrier targeting of BDNF improves motor function in rats with middle cerebral artery occlusion.
Intravenous brain-derived neurotrophic factor (BDNF) causes a 65-70% reduction in stroke volume in rats with the middle cerebral artery occlusion (MCAO), provided the BDNF is conjugated to a blood-brain barrier (BBB) molecular Trojan horse. The latter may be a peptidomimetic monoclonal antibody (MAb) to the transferrin receptor. The present studies determine whether the effects on stroke volume correlate with an improvement in neuro-behavior using the rotarod test. The rotarod latency was >200 s at 16 RPM in all rats pre-MCAO. The latency was 30+/-7 s and 103+/-9 s at 24 h post-MCAO in the animals treated with BDNF alone and the BDNF-MAb conjugate, respectively. These studies show that when BDNF is formulated to enable transport across the BBB, the intravenous administration of the neurotrophin results in a reduction in stroke volume that is associated with a parallel improvement in functional outcome.
Zhang
Yun
Y
Department of Medicine, UCLA Warren Hall 13-164, 900 Veteran Avenue, Los Angeles, CA 90024, USA.
Pardridge
William M
WM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000627:therapeutic use; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D007275:Injections, Intravenous; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009044:Motor Cortex / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D010291:Paresis / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects / Q000502:physiology; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D019208:Brain-Derived Neurotrophic Factor