ABSTRACT
Although the surface area of the BBB in the human brain is large [approximately 20 m2 (7)], small hydrophilic molecules cannot access the brain in pharmacologically adequate amounts when administered systemically or orally. This applies also to small peptidomimetic agents such as nerve growth factor (NGF)-mimetics (8) or neurotensine mimetics (9); hence effective delivery of these agents will require a drug delivery and targeting vehicle, or they should be conjugated to a BBB-targeting system. Development of novel drug delivery strategies requires adequate biological models to test their suitability. In vitro models include (i) primary cultures, (ii) immortalized neuronal, glial, and cerebromicrovascular endothelial cultures, (iii) hippocampal immortalized neuronal cultures (10,11), (iv) human cerebromicrovascular endothelial cell lines as a model of the BBB (12), and (v) more complex cocultures of neuronal and glial cells (13). In addition to these in vitro models, a number of in vivo model systems have been employed for testing neuroactive agents and their delivery systems. Rodent models, although indispensable and most commonly used to investigate neurological diseases, have limitations: (i) In general, they show some, but rarely all, of the pathological features of human neurological diseases; (ii) the time course of the progression of the disease is limited due to the difference in life span between two
species; and (iii) tests for verbal communication skills cannot be applied. A number of neurological disorders are associated with either a lack of neuroactive peptides (e.g., growth factors, neurotrophins) or malfunctioning of their receptors (defective binding between receptor and ligand, impaired internalization and transport of the receptor-ligand complex, or impaired signaling pathways downstream from the receptor site) (14-20). For example, abnormal growth factor levels in the CNS and/or PNS have been associated with Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and diabetic neuropathy (2124). Results from preclinical studies employing both in vitro and in vivo models discussed above suggest that individual growth factors (as representatives of hydrophilic molecules) can indeed correct, prevent, or delay some of the pathological features characteristic of diabetic neuropathy, Alzheimer’s, Parkinson’s, and Huntington’s diseases. However, due to the complexities involved in these pathologies, a simple replacement therapy employing drug delivery systems containing individual hydrophilic neurotherapeutics will most likely be used in conjunction with gene therapy and/or stem-cell therapies.
