Neurotrophins, neuroprotection and the blood-brain barrier

Small molecule drugs have not been effective neuroprotective agents in either the acute treatment of stroke or the chronic treatment of neurodegeneration. Thus, it is time to consider large molecule drugs such as recombinant neurotrophins. However, like many of the small molecules, neurotrophins do not cross the brain capillary endothelial wall, which forms the blood-brain barrier (BBB). Neurotrophins can be made transportable across the BBB by using chimeric peptide brain drug targeting technology, in which a neurotrophin is reformulated by fusion to a transport vector. The latter is a peptide or peptidomimetic monoclonal antibody that undergoes receptor-mediated transcytosis through the BBB, and acts as a 'molecular Trojan horse'. Neurotrophin chimeric peptides are highly neuroprotective following delayed intravenous administration, in both global and focal brain ischemia.