Chapter category: Neurodegenerative Disease
Blood-Brain Barrier Drug Targeting Enables Neuroprotection in Brain Ischemia Following Delayed Intravenous Administration of Neurotrophins
Molecular and Cellular Biology
of Neuroprotection in the CNS
Edited by: Christian AlzheimerISBN: 0-306-47414-X
» Get more information about this book at landesbioscience.com «
Chapter authors:
William M. Pardridge
The bloodbrain barrier (BBB) is the ratelimiting step in the translation of neurotrophin neuroscience into clinically effective neurotherapeutics. Since neurotrophins do not cross the BBB, these proteins cannot be used for neuroprotection following intravenous administration, and it is not feasible to administer these molecules by intra-cerebral injection in human stroke. The present studies describe the development of the chimeric peptide brain drug targeting technology and the use of brainderived neurotrophic factor (BDNF) chimeric peptides in either global or regional brain ischemia. The BDNF chimeric peptide is formed by conjugation of BDNF to a monoclonal antibody (MAb) to the BBB transferrin receptor, and the MAb acts as a molecular "Trojan Horse" to ferry the BDNF across the BBB via transport on the endogenous BBB transferrin receptor. High degrees of neuroprotection in transient forebrain ischemia, permanent middle cerebral artery occlusion, or reversible middle cerebral artery occlusion are achieved with the delayed intravenous administration of BDNF chimeric peptides. In contrast, no neuroprotection is observed following the intravenous administration of unconjugated BDNF, because the neurotrophin does not cross the BBB in vivo.
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